Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease?

Department of Clinical Neuroscience, University of Göteborg, Sweden.
Molecular and Chemical Neuropathology 01/1996; 26(3):231-45.
Source: PubMed


Cerebrospinal fluid (CSF) biochemical markers for Alzheimer disease (AD) would be of great value to improve the clinical diagnostic accuracy of the disorder. As abnormally phosphorylated forms of the microtubule-associated protein tau have been consistently found in the brains of AD patients, and since tau can be detected in CSF, two assays based on several well-defined monoclonal tau antibodies were used to study these proteins in CSF. One assay detects most normal and abnormal forms of tau (CSF-tau), while the other is highly specific for phosphorylated tau (CSF-PHFtau). A marked increase in CSF-PHFtau was found in AD (2230 +/- 930 pg/mL), as compared with controls (640 +/- 230 pg/mL; p < 0.0001), vascular dementia, VAD (1610 +/- 840 pg/mL; p < 0.05), frontal lobe dementia, FLD (1530 +/- 1000 pg/mL; p < 0.05), Parkinson disease, PD (720 +/- 590 pg/mL; p < 0.0001), and patients with major depression (230 +/- 130 pg/mL; p < 0.0001). Parallel results were obtained for CSF-tau. No less than 35/40 (88%) of AD patients had a CSF-PHFtau value higher than the cutoff level of 1140 pg/mL in controls. The present study demonstrates that elevated tau/PHFtau levels are consistently found in CSF of AD patients. However, a considerable overlap is still present with other forms of dementia, both VAD and FLD. CSF-tau and CSF-PHFtau may therefore be useful as a positive biochemical marker, to discriminate AD from normal aging, PD, and depressive pseudodementia. Further studies are needed to clarify the sensitivity and specificity of these assays, including follow-up studies with neuropathological examinations.

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    • "The collected CSF was used for analysis of T-tau, P-tau and Aβ1-42 at the Department of Clinical Neurochemistry, Mölndal Hospital. The T-tau concentration in CSF was determined using a sandwich ELISA (INNOTEST® hTAU Ag; Innogenetics, Gent, Belgium) specifically constructed to measure all tau isoforms irrespectively of phosphorylation status [28]. Tau phosphorylated at threonine 181 (P-tau181) was measured using a sandwich ELISA method [INNOTEST® PHOSPHO-TAU (181P); Innogenetics] [29]. "
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    ABSTRACT: Background The objective of this study was to examine the associations of agitation with the cerebrospinal fluid dementia biomarkers total-tau (T-tau), phosphorylated-tau (P-tau) and Aβ1-42. Methods One hundred patients (mean age ± SD, 78.6 ± 7.5 years) with dementia and neuropsychiatric symptoms, of whom 67% were female, were included. Agitation was measured using the Cohen-Mansfield Agitation Inventory (CMAI; 46.5 ± 11.8 points). Results Total CMAI correlated with T-tau [rs (31) = 0.36, p = 0.04] and P-tau [rs (31) = 0.35, p = 0.05] in patients with Alzheimer's disease (AD; n = 33) but not in the total dementia population (n = 95). Conclusions Our results suggest that tau-mediated pathology including neurofibrillary tangles and the intensity of the disease process might be associated with agitation in AD.
    08/2014; 4(2). DOI:10.1159/000363500
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    • "CSF A␤ 42 was analyzed by the electrochemiluminescence technology (Meso Scale Discovery, Gaithersburg, Maryland, USA), using the MS6000 Human Abeta 3-Plex Ultra-Sensitive Kit [20]. CSF T-tau was determined using a sandwich ELISA (Innotest hTAU-Ag, Fujirebio Europe, Gent, Belgium) specifically constructed to measure all tau isoforms irrespectively of phosphorylation status, as previously described [21], while P-tau (tau phosphorylated at threonine 181) was measured using the INNOTEST ® PHOSPHO-TAU 181P ELISA (Fujirebio Europe, Ghent, Belgium), as described previously in detail [22]. "
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    ABSTRACT: Objective: To compare cerebrospinal fluid (CSF) biomarkers and brain structure in preclinical mutation carriers (MC) and non-carriers (NC) from families with familial Alzheimer disease (FAD). Methods: The study included members from four Swedish families at risk for carrying an APPswe, APParc, PSEN1 H163Y or PSEN1 I143T mutation. Magnetic resonance imaging (MRI) scans were obtained from 13 MC and 20 NC and analyzed using vertex-based analyses of cortical thickness and volume. CSF was collected from 10 MC and 12 NC and analyzed for Aβ42, tau-protein and phospho-tau. Results: The MC had significantly lower levels of CSF Aβ42 and higher levels tau-protein and phospho-tau than the NC. There was a trend showing a decrease in Aβ42 15 – 20 years before expected onset of clinical symptoms, while a trend of increasing tau-protein and phospho-tau was observed closer to expected onset. The MC had decreased volume on MRI in the left precuneus, superior temporal gyrus and fusiform gyrus. Conclusions: Aberrant biomarker levels in CSF as well as regional brain atrophy are present in preclinical FAD, several years before the expected onset of clinical symptoms.
    Journal of Alzheimer's disease: JAD 08/2014; In-press. · 4.15 Impact Factor
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    • "Tau is a microtubule-associated protein that promotes and stabilizes microtubule assembly, and is primarily located in the axons of neuronal cells [18,19]. Increases in CSF t-tau indicate the severity of neuronal damage and loss [20]. CSF t-tau increases with age and the severity of clinical symptoms in iNPH, and tends to be lower in patients with good cognitive recovery after shunt surgery [21,22]. "
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    ABSTRACT: Idiopathic normal pressure hydrocephalus (iNPH) is a treatable cause of dementia, gait disturbance, and urinary incontinence in elderly patients with ventriculomegaly. Its unique morphological feature, called disproportionately enlarged subarachnoid-space hydrocephalus (DESH), may also be a diagnostic feature. Lipocalin-type prostaglandin D synthase (L-PGDS) is a major cerebrospinal fluid (CSF) protein produced by arachnoid cells, and its concentration in the CSF is reportedly decreased in iNPH. L-PGDS acts as a prostaglandin D2-producing enzyme and behaves as a chaperone to prevent the neurotoxic aggregation of amyloid beta (Abeta) implicated in Alzheimer's disease, a major comorbidity of iNPH. The aim of this study was to confirm the L-PGDS decrease in DESH-type iNPH and to clarify its relationship with clinico-radiological features or other CSF biomarkers. We evaluated 22 patients (age: 76.4 +/- 4.4 y; males: 10, females: 12) referred for ventriculomegaly without CSF pathway obstruction, and conducted a CSF tap test to determine the surgical indication. CSF concentrations of L-PGDS, Abeta42, Abeta40, and total tau (t-tau) protein were determined using enzyme-linked immunosorbent assays. Clinical symptoms were evaluated by the iNPH grading scale, mini-mental state examination, frontal assessment battery (FAB), and timed up and go test. The extent of DESH was approximated by the callosal angle, and the severity of parenchymal damage was evaluated by the age-related white matter change (ARWMC) score. L-PGDS and t-tau levels in CSF were significantly decreased in DESH patients compared to non-DESH patients (p = 0.013 and p = 0.003, respectively). L-PGDS and t-tau showed a significant positive correlation (Spearman r = 0.753, p < 0.001). Among the clinico-radiological profiles, L-PGDS levels correlated positively with age (Spearman r = 0.602, p = 0.004), callosal angle (Spearman r = 0.592, p = 0.004), and ARWMC scores (Spearman r = 0.652, p = 0.001), but were negatively correlated with FAB scores (Spearman r = 0.641, p = 0.004). Our data support the diagnostic value of L-PGDS as a CSF biomarker for iNPH and suggest a possible interaction between L-PGDS and tau protein. In addition, L-PGDS might work as a surrogate marker for DESH features, white matter damage, and frontal lobe dysfunction.
    Fluids and Barriers of the CNS 04/2014; 11(1):9. DOI:10.1186/2045-8118-11-9
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