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1.
Neurology ; 73(17): 1353-8, 2009 Oct 27.
Article in English | MEDLINE | ID: mdl-19858456

ABSTRACT

OBJECTIVE: CSF biomarkers amyloid beta 1-42 (Abeta(42)), total tau (tau), and tau phosphorylated at threonine 181 (p-tau-181) are useful diagnostic markers for Alzheimer disease (AD). Less is known about these biomarkers as predictors for further cognitive decline in patients with AD. We hypothesized that high tau, especially in combination with relatively low p-tau-181, is a marker of rapid decline, since it has been associated with fast neuronal degeneration. METHODS: A total of 151 patients with AD of whom we had baseline CSF were included from our memory clinic. All patients had at least 2 Mini-Mental State Examination (MMSE) scores, obtained no less than 1 year apart. Linear mixed models were used to assess associations between CSF biomarkers and the rate of cognitive decline as measured with the MMSE. CSF biomarkers were used in quintiles, random intercept and random slope with time were assumed, and the analyses were corrected for sex and age. RESULTS: The patients with AD (45% women, age 66 +/- 9 years, baseline MMSE 22 +/- 4) had a follow-up period of 2.0 (1.0-5.0) years. Linear mixed models revealed no relations between any CSF biomarker and baseline MMSE. However, CSF biomarkers did predict cognitive decline over time. A low p-tau-181/tau ratio was the strongest predictor with a dose-dependent effect (lowest vs highest quintile: 2.9 vs 1.3 MMSE points annual decline, p for trend <0.001). In addition, low Abeta(42), high tau, and high tau/Abeta(42)-ratio were associated with rapid cognitive decline (p < 0.05). CONCLUSION: At the time of diagnosis, a combination of high CSF tau without proportionally elevated p-tau-181 is associated with a faster rate of cognitive decline.


Subject(s)
Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Cognition Disorders/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Adult , Aged , Aged, 80 and over , Alzheimer Disease/diagnosis , Amino Acid Sequence , Biomarkers/cerebrospinal fluid , Cognition Disorders/diagnosis , Disease Progression , Female , Follow-Up Studies , Humans , Linear Models , Male , Middle Aged , Neuropsychological Tests , Phosphorylation , Prognosis , Severity of Illness Index , Time Factors , tau Proteins/genetics
2.
Neurology ; 69(10): 1006-11, 2007 Sep 04.
Article in English | MEDLINE | ID: mdl-17785669

ABSTRACT

OBJECTIVE: In Alzheimer disease (AD), longitudinal changes of beta-amyloid(1-42) (Abeta(1-42)), tau, and phosphorylated tau at threonine 181 (ptau-181) in CSF have been reported in small studies only. We evaluated the natural course of CSF biomarkers in patients with AD, subjective complaints, and mild cognitive impairment (MCI). METHODS: One hundred five patients (50 AD, 38 MCI, 17 subjective complaints) underwent two lumbar punctures, with a mean interval of 21 +/- 9 months. CSF levels of Abeta(1-42), tau, and ptau-181 were measured. RESULTS: CSF Abeta(1-42) and tau levels showed main effects for both diagnosis and time (all p < 0.05), with average increases of 47 +/- 72 and 49 +/- 143 pg/mL. The interaction terms were not significant, which implies a similar time effect for all diagnostic groups. CSF ptau-181 levels showed a main effect for diagnosis (p = 0.01) but not for time (p = 0.27, increase of 1.0 +/- 12 pg/mL). CONCLUSION: Levels of CSF beta-amyloid(1-42) and tau but not phosphorylated tau at threonine 181 increased over time in this memory clinic patient cohort with comparable change in all diagnostic groups. The cross-sectional difference between diagnostic groups, however, exceeded by far the longitudinal changes within individuals, suggesting that these biomarkers are not sensitive as markers of disease progression.


Subject(s)
Biomarkers/cerebrospinal fluid , Memory/physiology , Outpatient Clinics, Hospital/trends , Aged , Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Cognition Disorders/cerebrospinal fluid , Cohort Studies , Female , Follow-Up Studies , Humans , Longitudinal Studies , Male , Middle Aged , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluid
3.
Neurobiol Aging ; 28(7): 1070-4, 2007 Jul.
Article in English | MEDLINE | ID: mdl-16782233

ABSTRACT

OBJECTIVE: To study CSF biomarkers, beta-amyloid(1-42) (Abeta(1-42)) and tau, and medial temporal lobe atrophy (MTA) on MRI in their ability to predict dementia in patients with mild cognitive impairment (MCI). METHODS: Fifty-nine MCI patients (49% male, mean age 69+/-8), follow-up 19 months, were included. Baseline CSF levels of Abeta(1-42), tau and MTA-score were dichotomized. RESULTS: Thirty-three (56%) of the MCI patients progressed to dementia, 30 of which had Alzheimer's disease. Lower CSF Abeta(1-42) level, higher CSF-tau and higher MTA-scores at baseline were found in progressed patients. Cox proportional hazards models revealed that abnormal CSF Abeta(1-42), CSF tau and MTA were significantly associated with dementia at follow-up (hazard ratio (95% confidence interval): 4.0 (1.3-12.1), 5.9 (1.6-21.7) and 2.1 (1.0-4.6)). A fourfold higher risk was found for patients with both abnormal CSF biomarkers and MTA compared to patients with either test abnormal. Ninety-four percent of patients with both abnormalities converted to dementia. CONCLUSIONS: These findings suggest an added value of CSF to MRI in the diagnostic work up of patients presenting at a memory clinic.


Subject(s)
Amyloid beta-Peptides/cerebrospinal fluid , Cognition Disorders/cerebrospinal fluid , Cognition Disorders/pathology , Dementia/diagnosis , Peptide Fragments/cerebrospinal fluid , Temporal Lobe/pathology , Aged , Atrophy , Disease Progression , Female , Humans , Longitudinal Studies , Magnetic Resonance Imaging/methods , Male , Middle Aged , Predictive Value of Tests , Prospective Studies , tau Proteins/cerebrospinal fluid
4.
Neurocase ; 11(1): 8-13, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15804919

ABSTRACT

The aim of the study was to compare clinical variables between MCI patients at different risk for Alzheimer's disease (AD) according to their biomarker profile. Fifty-four percent out of 39 MCI patients had a low Abeta42 and high tau in cerebrospinal fluid (CSF) (high-risk), 26% either a low CSF Abeta32 or high CSF tau (intermediate-risk) and 20% a normal CSF Abeta42 and tau (low-risk). Both high-and intermediate-risk subjects differed from the low-risk group in episodic memory, executive functions and the preclinical AD scale (PAS),which combines a set of clinical parameters. Subjects at high risk did not differ from subjects with an intermediate risk. Abeta42 levels correlated with the MTA and PAS scores, tau levels with episodic memory. These correlations suggest that the biomarkers are not independent when compared to the other AD markers. Longitudinal studies are necessary to interpret the correlations between biomarkers, imaging, and neuropsychological markers.


Subject(s)
Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Cognition Disorders/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Aged , Aged, 80 and over , Alzheimer Disease/complications , Alzheimer Disease/pathology , Apolipoproteins E/genetics , Biomarkers/cerebrospinal fluid , Cognition Disorders/etiology , Cognition Disorders/pathology , Female , Genotype , Humans , Linear Models , Magnetic Resonance Imaging/methods , Male , Memory/physiology , Mental Status Schedule/statistics & numerical data , Middle Aged , Neuropsychological Tests/statistics & numerical data , Problem Solving/physiology , Retrospective Studies , Risk , Statistics, Nonparametric
5.
Neurology ; 62(9): 1580-4, 2004 May 11.
Article in English | MEDLINE | ID: mdl-15136685

ABSTRACT

OBJECTIVE: To determine the diagnostic value of CSF amyloid beta(1-42) (Abeta42), CSF total tau, and CSF tau phosphorylated at threonine-181 (Ptau-181) in early-onset Alzheimer disease (EAD) vs frontotemporal lobar degeneration (FTLD). METHODS: Levels of Abeta42, total tau, and Ptau-181 in CSF were measured using commercially available ELISA in 47 EAD patients, 28 FTLD patients, and 21 nondemented control subjects. RESULTS: CSF Abeta42 was significantly lower and CSF total tau and CSF Ptau-181 significantly higher in EAD patients than FTLD patients and control subjects. There was an increase in diagnostic accuracy for CSF Ptau-181 vs CSF total tau (p = 0.067). Combining low CSF Abeta42 and high CSF Ptau-181 allowed EAD patients to be distinguished from FTLD patients with a sensitivity of 72% and a specificity of 93%. Logistic regression analysis with CSF Abeta42 and CSF Ptau-181 as independent continuous variables resulted in correct classification of 46 of 47 (98%) EAD patients and 23 of 28 (82%) FTLD patients. The diagnostic accuracy for EAD was independent of gender, disease duration, and disease severity. CONCLUSION: The combination of CSF Abeta42 and CSF Ptau-181 may help in differentiating EAD from FTLD.


Subject(s)
Alzheimer Disease/cerebrospinal fluid , Amyloid beta-Peptides/cerebrospinal fluid , Dementia/cerebrospinal fluid , Peptide Fragments/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Aged , Alzheimer Disease/diagnosis , Apolipoproteins E/cerebrospinal fluid , Biomarkers/cerebrospinal fluid , Dementia/diagnosis , Diagnosis, Differential , Enzyme-Linked Immunosorbent Assay , Female , Humans , Logistic Models , Male , Middle Aged , Neurofilament Proteins/chemistry , Phosphorylation , Plaque, Amyloid/chemistry , Sensitivity and Specificity , Severity of Illness Index , Sex Factors
6.
Growth Regul ; 6(4): 238-46, 1996 Dec.
Article in English | MEDLINE | ID: mdl-8971553

ABSTRACT

Osteoblast-like UMR-106.01 rat osteosarcoma cells express high affinity growth hormone (GH) receptors (GHRs). Because osteoblasts secrete insulin-like growth factor binding protein-5 (IGFBP-5), we evaluated whether it also modulates GH binding and GHR expression in UMR cells. Human recombinant intact IGFBP-5 stimulated 125I-hGH binding in a dose-dependent manner (dose range 300-3000 ng/ml), inducing an increase to 193.6 +/- 2.1% of control binding at 3000 ng/ml (P < 0.001). Carboxy-truncated IGFBP-5 also stimulated GH binding but with less potency (125 +/- 2.7% of control at 3000 ng/ml, P < 0.01). GHRs identified by chemical crosslinking of 125I-hGH to cell monolayers increased after treatment with IGFBP-5 and decreased in response to insulin-like growth factor-I (IGF-I). GHR mRNA levels, as quantitated by a solution hybridization RNAse protection assay, increased up to 3 to 7-fold in a time-dependent manner by intact IGFBP-5 but not by carboxy-truncated IGFBP-5. An antiserum to IGFBP-5 reduced basal GH binding to 56.7 +/- 4.3% of control value at a concentration of 0.5% (P < 0.001), showing that IGFBP-5 produced by the cells is a strong regulator of GH binding. IGFBP-5 antiserum also decreased GH binding to 85.9 +/- 0.9% of IGFBP-5 stimulated value (P < 0.001), showing the specificity of IGFBP-5 stimulation. To determine whether the GHR upregulation was physiologically significant, cell proliferation was evaluated after coincubation of IGFBP-5 with low, non-stimulatory concentrations of GH. IGFBP-5 (1000 ng/ml) induced cell proliferation to 116.2 +/- 3.2% of control levels, and coincubation with hGH at 10 ng/ml induced an increase to 133.3 +/- 0.1% of control levels. We conclude that exogenous and endogenous IGFBP-5 upregulate GHR mRNA levels and GH binding and this interaction potentiates GH-stimulated mitogenesis in osteoblastic cells.


Subject(s)
Bone Neoplasms/metabolism , Insulin-Like Growth Factor Binding Protein 5/pharmacology , Osteosarcoma/metabolism , Receptors, Somatotropin/drug effects , Animals , Cell Division/drug effects , Cell Line , Cross-Linking Reagents , Growth Hormone/pharmacology , Humans , Iodine Radioisotopes , Isotope Labeling , Radioligand Assay , Rats , Ribonucleases/metabolism , Tumor Cells, Cultured
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