CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects

Büerger, Katharina; Teipel, Stefan J.; Zinkowski, Raymond; Blennow, Kaj; Arai, Hiroyuki; Engel, Rolf R.; Hofmann-Kiefer, Klaus; McCulloch, Cheryl; Ptok, Ursula; Heun, Reiner; Andreasen, Niels; DeBernardis, John F.; Kerkman, Daniel J.; Moeller, Hans‐Juergen; Davies, Peter; Hampel, Harald

doi:10.1212/wnl.59.4.627

Cited by 221 publications

(131 citation statements)

References 10 publications

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“…to assume that there is no difference between groups despite a true difference of markers in the population. Our results, however, showing significantly lower levels of CSF p-tau 231 and t-tau in HC subjects compared to AD patients as well as extremely high t-tau values in CJD compared to other diagnostic entities are in accordance with the literature [2,3,4,7,11,15]. The main findings of our study refer to the CJD and the AD groups, i.e.…”

Section: Discussionsupporting

confidence: 92%

“…Highly significant increases in CSF p-tau in AD patients have recently been demonstrated in independent studies, mainly using three different immunoassays specific for the phosphorylated epitopes threonine 231 (p-tau 231 ) [12], threonine 181 (p-tau 181 ) [22], and serine 199 (p-tau 199 ) [10]. Evidence from these studies indicates that quantification of tau phosphorylated at these specific sites may improve early detection (as a prognostic and diagnostic marker) [2], differential diagnosis (as a classificatory marker) [3,4,7,18], and tracking of disease progression in AD (for review see [1,8]). Therefore, CSF measurement of p-tau proteins comes closest to fulfilling criteria of a core feasible biomarker of AD [5].…”

Section: Introductionmentioning

confidence: 98%

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Dissociation between CSF total tau and tau protein phosphorylated at threonine 231 in Creutzfeldt–Jakob disease

Büerger

Otto

Teipel

et al. 2006

Neurobiology of Aging

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To study the potential diagnostic value of abnormally phosphorylated tau protein in Creutzfeldt-Jakob disease (CJD) compared to Alzheimer's disease (AD), we determined levels of tau phosphorylated at threonine 231 (p-tau 231 ) and of total tau (t-tau) in cerebrospinal fluid (CSF) of CJD patients, AD patients, and healthy controls (HC). CJD patients showed excessively high t-tau levels but relatively low p-tau 231 concentrations compared to the AD group. t-tau alone yielded the best diagnostic accuracy to differentiate between CJD and AD patients, when compared to p-tau 231 and the p-tau 231 /t-tau ratio (97, 78, and 95% correctly allocated cases, respectively). Our findings indicate a dissociation in the direction of change in CSF levels of t-tau and p-tau 231 in CJD when compared to AD.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 98%

Dissociation between CSF total tau and tau protein phosphorylated at threonine 231 in Creutzfeldt–Jakob disease

Büerger

Otto

Teipel

et al. 2006

Neurobiology of Aging

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“…Immunoblotting revealed site-specific Tau hyperphosphorylation at Thr-231 but not at Ser-202. Phosphorylation of Tau at Thr-231 in humans has been correlated with cognitive decline and suggested as a biomarker for Alzheimer's disease (17). These findings in NIRKO mice are in contrast to those obtained in mice lacking IRS-2, which also exhibit Tau hyperphosphorylation, but this occurs exclusively at Ser-202 (18), a presumed site of cyclin-dependent kinase phosphorylation (19).…”

Section: Resultsmentioning

confidence: 96%

Role for neuronal insulin resistance in neurodegenerative diseases

Schubert

Gautam

Surjo

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

560

313

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Impairment of insulin signaling in the brain has been linked to neurodegenerative diseases. To test the hypothesis that neuronal insulin resistance contributes to defects in neuronal function, we have performed a detailed analysis of brain͞neuron-specific insulin receptor knockout (NIRKO) mice. We find that NIRKO mice exhibit a complete loss of insulin-mediated activation of phosphatidylinositol 3-kinase and inhibition of neuronal apoptosis. In intact animals, this loss results in markedly reduced phosphorylation of Akt and GSK3␤, leading to substantially increased phosphorylation of the microtubule-associated protein Tau, a hallmark of neurodegenerative diseases. Nevertheless, these animals exhibit no alteration in neuronal proliferation͞survival, memory, or basal brain glucose metabolism. Thus, lack of insulin signaling in the brain may lead to changes in Akt and GSK3␤ activity and Tau hyperphosphorylation but must interact with other mechanisms for development of Alzheimer's disease.

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“…Elevated levels of tau phosphorylated at threonine 231 (p-tau 231 ), old age, and apolipoprotein E e4 carrier status, but not total tau (t-tau), predicted cognitive decline and conversion to AD in 77 MCI subjects. 31 Levels of p-tau doubly phosphorylated at threonine 231 and serine 235 were elevated in MCI subjects compared to controls with subjective memory complaints. 32 From that data and the results presented here, it might be assumed that among the three biomarkers Ab 1-42, ttau, and p-tau, t-tau might be the least sensitive to predict AD in MCI.…”

Section: Discussionmentioning

confidence: 95%

Value of CSF β-amyloid1–42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment

Hampel¹,

Teipel²,

Fuchsberger³

et al. 2003

Mol Psychiatry

285

196

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Subjects with mild cognitive impairment (MCI) are at a high risk of developing clinical Alzheimer's disease (AD). We asked to what extent the core biomarker candidates cerebro-spinal fluid (CSF) bamyloid 1-42 (Ab 1-42 ) and CSF tau protein concentrations predict conversion from MCI to AD. We studied 52 patients with MCI, 93 AD patients, and 10 healthy controls (HC). The MCI group was composed of 29 patients who had converted to AD during follow-up, and of 23 patients who showed no cognitive decline. CSF Ab 1-42 and tau protein levels were assessed at baseline in all subjects, using enzyme-linked immunosorbent assays. For assessment of sensitivity and specificity, we used independently established reference values for CSF Ab 1-42 and CSF tau. The levels of CSF tau were increased, whereas levels of Ab 1-42 were decreased in MCI subjects. Ab 1-42 predicted AD in converted MCI with a sensitivity of 59% and a specificity of 100% compared to HC. Tau yielded a greater sensitivity of 83% and a specificity of 90%. In a multiple Cox regression analysis within the MCI group, low baseline levels of Ab 1-42 , but not other predictor variables (tau protein, gender, age, apolipoprotein E e4 carrier status, Mini Mental Status Examination score, observation time, antidementia therapy), correlated with conversion status (Po0.05). Our findings support the notion that CSF tau and Ab 1-42 may be useful biomarkers in the early identification of AD in MCI subjects.

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CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects

Cited by 221 publications

References 10 publications

Dissociation between CSF total tau and tau protein phosphorylated at threonine 231 in Creutzfeldt–Jakob disease

Dissociation between CSF total tau and tau protein phosphorylated at threonine 231 in Creutzfeldt–Jakob disease

Role for neuronal insulin resistance in neurodegenerative diseases

Value of CSF β-amyloid1–42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment

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