Saturday, January 14, 2012

phosphorylated tau | What is phosphorylated tau|Papers on phosphorylated tau|Research on phosphorylated tau| Publications on phosphorylated tau


1.
J Alzheimers Dis. 2012 Jan 9. [Epub ahead of print]

Performance of Aβ1-40, Aβ1-42, Total Tau, and Phosphorylated Tau as Predictors of Dementia in a Cohort of Patients with Mild Cognitive Impairment.

Source

Clinica Neurologica, Università degli Studi di Perugia, Italy.

Abstract

Mild cognitive impairment (MCI) is a common condition in the elderly which may remain stable along time (MCI-MCI) or evolve into Alzheimer's disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, i.e., amyloid-β 1-42 (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect the neuropathological changes taking place in AD brains, thus disclosing the disease in its prodromal phase. With the aim to evaluate the power of each biomarker and/or their combination in predicting AD progression, we have measured CSF Aβ1-40, Aβ1-42, t-tau, and p-tau in patients with AD, MCI-MCI, MCI-AD, and other neurological diseases without dementia (OND) followed up for four years. Aβ1-42 levels were significantly lower in AD and MCI-AD than in MCI-MCI. T-tau and p-tau levels were significantly increased in AD and MCI-AD versus OND and MCI-MCI. The Aβ1-42/Aβ1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Aβ1-42/t-tau and Aβ1-42/p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Aβ1-42/p-tau ratio was the best parameter for discriminating MCI-AD from MCI-MCI (sensitivity 81%, specificity 95%), being also correlated with the annual change rate in the Mini Mental State Examination score (MMSE-ACR, rS = -0.71, p < 0.0001). Survival analysis showed that 81% of MCI with a low Aβ1-42/p-tau ratio (<1372) progressed to AD. The best model of logistic regression analysis retained Aβ1-42 and p-tau (sensitivity 75%, 95%CI: 70-80%; specificity 96%, 95%CI: 94-98%). We can conclude that Aβ1-42 and p-tau reliably predict conversion to AD in MCI patients.

PMID:
22232006
[PubMed - as supplied by publisher]
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2.
Chemistry. 2012 Jan 9. doi: 10.1002/chem.201103032. [Epub ahead of print]

The Alzheimer's Disease Related Tau Protein as a New Target for Chemical Protein Engineering.

Source

Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin (Germany), Fax: (+49) 30-838-52551.

Abstract

Site-specifically phosphorylated tau: A semisynthetic strategy has been applied for the first time to generate aphosphorylated and biotinylated fully functional tau protein. The presented methodology allows for an unambiguous verification of individual phosphorylation sites on tau and significantly improves its purification.

Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PMID:
22231520
[PubMed - as supplied by publisher]
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3.
J Alzheimers Dis. 2012 Jan 3. [Epub ahead of print]

Amyloid-β Oligomers in Cerebrospinal Fluid are Associated with Cognitive Decline in Patients with Alzheimer's Disease.

Source

Department of Cardiothoracic Surgery of the Martin-Luther-University Halle-Wittenberg, Halle, Germany.

Abstract

Oligomers of the amyloid-β peptide (Aβ) are thought to be the most toxic form of Aβ and are linked to the development of Alzheimer's disease (AD). Here, we used a flow cytometric approach for the detection and assessment of oligomers in cerebrospinal fluid (CSF) from AD patients and other neurological disorders. 30 CSF samples from patients suffering from AD (n = 14), non-demented controls (n = 12), and other neurological disorders (dementia with Lewy bodies, n = 2; vascular dementia, n = 1; primary progressive aphasia, n = 1) were analyzed for the presence of Aβ-oligomers by flow cytometry. The CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ)42 were determined using ELISA. CSF Aβ-oligomer levels in AD patients were elevated in comparison to the non-AD group (p = 0.073). The ratio Aβ-oligomers/Aβ42 was significantly elevated in AD subjects compared to non-AD subjects (p = 0.001). Most important, there was a negative correlation between the amount of Aβ-oligomers and the Mini-Mental Status Exam score (r = -0.65; p = 0.013) in AD patients. The detection of Aβ-oligomers using flow cytometry analysis seems to be useful in assessing the stage of AD. This is a novel and important finding as none of the currently used CSF biomarkers are clearly associated with dementia severity.

PMID:
22214781
[PubMed - as supplied by publisher]
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4.
Arch Gen Psychiatry. 2012 Jan;69(1):98-106.

Cerebrospinal Fluid Levels of β-Amyloid 1-42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia.

Source

Neuropsychiatric Clinic, Skåne University Hospital, S-20502 Malmö, Sweden. oskar.hansson@med.lu.se.

Abstract

CONTEXT:

Early detection of prodromal Alzheimer disease (AD) is important because new disease-modifying therapies are most likely to be effective when initiated during the early stages of disease.

OBJECTIVES:

To assess the ability of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau(P-tau), and β-amyloid 1-42 (Aβ42) to predict future development of AD dementia within 9.2 years in patients with mild cognitive impairment (MCI) and to compare CSF biomarkers between early and late converters to AD.

DESIGN:

A clinical study with a median follow-up of 9.2 years (range, 4.1-11.8 years).

SETTING:

Memory disorder clinic. Patients A total of 137 patients with MCI who underwent lumbar puncture at baseline. Main Outcome Measure Conversion to AD dementia.

RESULTS:

During follow-up, 72 patients (53.7%) developed AD and 21 (15.7%) progressed to other forms of dementia. At baseline, CSF Aβ42 levels were reduced and T-tau and P-tau levels were elevated in patients who converted to AD during follow-up compared with nonconverters (P < .001). Baseline CSF Aβ42 levels were equally reduced in patients with MCI who converted to AD within 0 to 5 years (early converters) compared with those who converted between 5 and 10 years (late converters). However, CSF T-tau and P-tau levels were significantly higher in early converters vs late converters. A baseline Aβ42:P-tau ratio predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91%, and negative predictive value of 86%.

CONCLUSIONS:

Approximately 90% of patients with MCI and pathologic CSF biomarker levels at baseline develop AD within 9 to 10 years. Levels of Aβ42 are already fully decreased at least 5 to 10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Aβ metabolism precedes tau-related pathology and neuronal degeneration.

PMID:
22213792
[PubMed - in process]
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5.
Cytometry A. 2011 Dec 28. doi: 10.1002/cyto.a.22009. [Epub ahead of print]

Isolation of synaptic terminals from Alzheimer's disease cortex.

Source

UCLA School of Nursing, Los Angeles, California 90095; UCLA Center for the Advancement of Gerontological Nursing Sciences, Los Angeles, California 90095; UCLA Brain Research Institute, Los Angeles, California 90095. ssokolow@sonnet.ucla.edu.

Abstract

Amyloid beta (Aβ) oligomers and phosphorylated tau (p-tau) aggregates are increasingly identified as potential toxic intermediates in Alzheimer's disease (AD). In cortical AD synapses, p-tau co-localizes with Aβ, but the Aβ and p-taupeptide species responsible for synaptic dysfunction and demise remains unclear. The present experiments were designed to use high-speed cell sorting techniques to purify synaptosome population based on size, and then extend the method to physically isolate Aβ-positive synaptosomes with the goal of understanding the nature of Aβ and taupathology in AD synapses. To examine the purity of size-gated synaptosomes, samples were first gated on size; particles with sizes between 0.5 and 1.5 microns were collected. Electron microscopy documented a homogenous population of spherical particles with internal vesicles and synaptic densities. Next, size-gated synaptosomes positive for Aβ were collected by fluorescence activated sorting and then analyzed by immunoblotting techniques. Sorted Aβ-positive synaptosomes were enriched for amyloid precursor protein (APP) and for Aβ oligomers and aggregates; immunolabeling for p-tau showed a striking accumulation of p-tau aggregates compared to the original homogenate and purified synaptosomes. These results confirm co-localization of Aβ and p-tau within individual synaptic terminals and provide proof of concept for the utility of flow sorting synaptosomes. © 2011 International Society for Advancement of Cytometry.

Copyright © 2011 International Society for Advancement of Cytometry.

PMID:
22213704
[PubMed - as supplied by publisher]
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6.
Neurologia. 2011 Dec 23. [Epub ahead of print]

Does Alzheimer's disease exist in all primates? Alzheimer pathology in non-human primates and its pathophysiological implications (I).

[Article in English, Spanish]

Source

Instituto Cajal, CSIC, Madrid, España.

Abstract

INTRODUCTION:

Many publications consider that the Alzheimer's disease (AD) is exclusive to the human species, and that no other animal species suffers from the disease. However, various studies have shown that some species can present with some of the defining characteristics of the disease in humans, both in the neuropathological changes and cognitive-behavioural symptoms.

DEVELOPMENT:

In this work, the results published (PubMed) on the senile brain changes in non-human primates of different degrees of evolution, are reviewed. The neuropathological changes associated with the accumulation of amyloid or highly phosphorylated tau protein are rare outside the primate order, but in all the sub-orders, families, genera and species of non-human primates that have been studied, some senile individuals have shown amyloid accumulation in the brain. Even in some species the presence of these deposits in senility is constant. Changes related to the accumulation of tau protein, are always of very little significance, and have been detected only in some non-human primate species, both little evolved and highly evolved. In different species of non-human primates, some types of cognitive-behavioural changes are present in some senile individuals with greater intensity when compared with both normal adult individuals and other senile individuals of the species. The importance of the determination of the longevity of the species in different habitats (natural habitats, new habitats, semi-liberty, captivity) is stressed in these studies.

CONCLUSIONS:

Morphological and histochemical and cognitive-behavioural features similar to those observed in normal aged man are present in senile non-human primates. Moreover, other characteristics of the non-human primates could be indicative of a pathological «Alzheimer type» ageing.

Copyright © 2011 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

PMID:
22197064
[PubMed - as supplied by publisher]
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7.
Cell Death Differ. 2011 Dec 23. doi: 10.1038/cdd.2011.188. [Epub ahead of print]

WW domain-containing oxidoreductase promotes neuronal differentiation via negative regulation of glycogen synthase kinase 3β

Source

Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan.

Abstract

WW domain-containing oxidoreductase (WWOX), a putative tumour suppressor, is suggested to be involved in the hyperphosphorylation of Alzheimer's Tau. Tau is a microtubule-associated protein that has an important role in microtubule assembly and stability. Glycogen synthase kinase 3β (GSK3β) has a vital role in Tau hyperphosphorylation at its microtubule-binding domains. Hyperphosphorylated Tau has a low affinity for microtubules, thus disrupting microtubule stability. Bioinformatics analysis indicated that WWOX contains two potential GSK3β-binding FXXXLI/VXRLE motifs. Immunofluorescence, immunoprecipitation and molecular modelling showed that WWOX interacts physically with GSK3β. We demonstrated biochemically that WWOX can bind directly to GSK3β through its short-chain alcohol dehydrogenase/reductase domain. Moreover, the overexpression of WWOX inhibited GSK3β-stimulated S396 and S404 phosphorylation within the microtubule domains of Tau, indicating that WWOX is involved in regulating GSK3β activity in cells. WWOX repressed GSK3β activity, restored the microtubule assembly activity of Tau and promoted neurite outgrowth in SH-SY5Y cells. Conversely, RNAi-mediated knockdown of WWOX in retinoic acid (RA)-differentiated SH-SY5Y cells inhibited neurite outgrowth. These results suggest that WWOX is likely to be involved in regulating GSK3β activity, reducing the level of phosphorylated Tau, and subsequently promoting neurite outgrowth during neuron differentiation. In summary, our data reveal a novel mechanism by which WWOX promotes neuronal differentiation in response to RA.Cell Death and Differentiation advance online publication, 23 December 2011; doi:10.1038/cdd.2011.188.

PMID:
22193544
[PubMed - as supplied by publisher]
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8.
Neurology. 2011 Dec 21. [Epub ahead of print]

Amyloid pathology in persons with "normal" cognition.

Source

From the Rush Alzheimer's Disease Center, Department of Neurological Sciences, Rush University Medical Center, Chicago, IL.

Abstract

Alzheimer disease (AD) is characterized pathologically by cortical neuritic plaques composed of a central core of amyloid-β (Aβ) peptide fibrils and neurofibrillary tangles composed of abnormally phosphorylated tau. The deposition of Aβ is thought to be an early step in a cascade of events that ultimately leads to the loss of cognitive abilities and dementia that characterizes AD. Thus, it was not surprising to find AD pathology in persons with mild cognitive impairment (MCI).(1) Clinical-pathologic studies have also reported a relation between AD pathology and cognition in persons without MCI or dementia.(2) Over the past several years, clinical-pathologic studies have been confirmed with in vivo imaging of amyloid by PET using Pittsburgh compound B (PiB).(3) Overall, these findings have led to a new conceptualization of AD as beginning with an asymptomatic pathophysiologic process, followed by a MCI stage, and ultimately the final AD dementia stage.(4,5) Understanding factors that influence the onset and progression of AD is of great interest. The apolipoprotein E ε4 allele polymorphism (APOE) is the most important genetic risk factor for AD and may increase disease risk, in part, by influencing Aβ clearance and fibrillogenesis.(6) In fact, some clinical-pathologic data suggest that Aβ mediates the association of APOE with cognition, at least in studies that include the full range of cognition.(7) However, the influence of APOE on Aβ and cognition among persons without cognitive impairment has not been well studied. In this issue of Neurology®, Kantarci et al.(8) use data from the Mayo Clinic Study of Aging (MCSA) to examine the relation of APOE to Aβ identified by PiB PET imaging and cognitive function in persons without cognitive impairment.

PMID:
22189449
[PubMed - as supplied by publisher]
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9.
J Neurosci Res. 2011 Dec 20. doi: 10.1002/jnr.22808. [Epub ahead of print]

Effect of chronic administration of estradiol, progesterone, and tibolone on the expression and phosphorylation of glycogen synthase kinase-3β and the microtubule-associated protein tau in the hippocampus and cerebellum of female rat.

Source

Unidad de Investigación Médica en Farmacología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México.

Abstract

Gonadal hormones regulate expression and activation of protein tau. Tibolone is a drug used as first- choice comprehensive treatment for the relief of menopausal symptoms, because it and its various metabolites have estrogenic properties and progestogenic/androgenic effects; however, the effect on the activation of tau protein and its signaling cascade in the brain is unknown. We studied the effect of chronic administration of estradiol (E2), progesterone (P4), and tibolone (TIB) on the expression and phosphorylation of microtubule-associated protein tau and glycogen synthase kinase-3β (GSK3β) in the hippocampus and cerebellum of ovariectomized rats. Ovariectomized adult female rats were implanted with pellets of vehicle, E2, or P4 or were treated with TIB by oral administration for 60 days. The animals were sacrificed, and tissue proteins were analyzed by Western blot. We observed that, in the hippocampus, administration of E2, P4, or TIB significantly decreased the protein content of hyperphosphorylated tau and increased the taudephosphorylated form, whereas only treatment with TIB increased the content of the phosphorylated form of GSK3β. In the cerebellum, E2 and TIB treatments resulted in a significant decrease in the expression of hyperphosphorylated tau, whereas E2 and TIB increased phosphorylated GSK3β; P4 had no effect. These results indicate that chronic administration of gonadal hormones and tibolone modulates tau and GSK3β phosphorylation in hippocampus and cerebellum of the rat and may exert a neuroprotective effect in these tissues. © 2011 Wiley Periodicals, Inc.

Copyright © 2011 Wiley Periodicals, Inc.

PMID:
22183707
[PubMed - as supplied by publisher]
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10.
Neurology. 2012 Jan 3;78(1):55-61. Epub 2011 Dec 14.

Cerebrospinal fluid amyloid β and tau in LRRK2 mutation carriers.

Source

Correspondence & reprint requests to Dr. Zhang: zhangj@uw.edu.

Abstract

OBJECTIVE:

The goal of the current investigation was to examine a cohort of symptomatic and asymptomatic LRRK2 mutation carriers, in order to address whether the reported alterations in amyloid β (Aβ) and tau species in the CSF of patients with sporadic Parkinson disease (PD) are a part of PD pathogenesis, the aging process, or a comorbid disease in patients with PD, and to explore the possibility of Aβ and tau as markers of early or presymptomatic PD.

METHODS:

CSF Aβ42, total tau, and phosphorylated tau were measured with Luminex assays in 26 LRRK2 mutation carriers, who were either asymptomatic (n = 18) or had a phenotype resembling sporadic PD (n = 8). All patients also underwent PET scans with (18)F-6-fluoro-l-dopa (FD), (11)C-(±)-α-dihydrotetrabenazine (DTBZ), and (11)C-d-threo-methylphenidate (MP) to measure dopaminergic function in the striatum. The levels of CSF markers were then compared to each PET measurement.

RESULTS:

Reduced CSF Aβ42 and tau levels correlated with lower striatal dopaminergic function as determined by all 3 PET tracers, with a significant association between Aβ42 and FD uptake. When cases were restricted to carriers of the G2019S mutation, the most common LRRK2 variant in our cohort, significant correlations were also observed for tau.

CONCLUSIONS:

The disposition of Aβ and tau is likely important in both LRRK2-related and sporadic PD, even during early phases of the disease. A better understanding of their production, aggregation, and degradation, including changes in their CSF levels, may provide insights into the pathogenesis of PD and the potential utility of these proteins as biomarkers.

PMID:
22170881
[PubMed - in process]
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11.
Neurology. 2012 Jan 3;78(1):47-54. Epub 2011 Dec 14.

Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort.

Source

Correspondence and reprint requests to Dr. Schoonenboom: niki.schoonenboom@vumc.nl.

Abstract

OBJECTIVE:

To determine how amyloid β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) levels in CSF behave in a large cohort of patients with different types of dementia.

METHODS:

Baseline CSF was collected from 512 patients with Alzheimer disease (AD) and 272 patients with other types of dementia (OD), 135 patients with a psychiatric disorder (PSY), and 275 patients with subjective memory complaints (SMC). Aβ42, t-tau, and p-tau (at amino acid 181) were measured in CSF by ELISA. Autopsy was obtained in a subgroup of 17 patients.

RESULTS:

A correct classification of patients with AD (92%) and patients with OD (66%) was accomplished when CSF Aβ42 and p-tau were combined. Patients with progressive supranuclear palsy had normal CSF biomarker values in 90%. Patients with Creutzfeldt-Jakob disease demonstrated an extremely high CSF t-tau at a relatively normal CSF p-tau. CSF AD biomarker profile was seen in 47% of patients with dementia with Lewy bodies (DLB), 38% in corticobasal degeneration (CBD), and almost 30% in frontotemporal lobar degeneration (FTLD) and vascular dementia (VaD). PSY and SMC patients had normal CSF biomarkers in 91% and 88%. Older patients are more likely to have a CSF AD profile. Concordance between clinical and neuropathologic diagnosis was 85%. CSF markers reflected neuropathology in 94%.

CONCLUSION:

CSF Aβ42, t-tau, and p-tau are useful in differential dementia diagnosis. However, in DLB, FTLD, VaD, and CBD, a substantial group exhibit a CSF AD biomarker profile, which requires more autopsy confirmation in the future.

PMID:
22170879
[PubMed - in process]
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12.
Alzheimer Dis Assoc Disord. 2011 Dec 7. [Epub ahead of print]

Cerebrospinal Fluid Proteins Predict Longitudinal Hippocampal Degeneration in Early-stage Dementia of the Alzheimer Type.

Source

*Northwestern University Feinberg School of Medicine, Chicago, IL †Washington University School of Medicine, St. Louis, MO ‡Simon Frasier University, Vancouver, BC, Canada.

Abstract

OBJECTIVE:

Biomarkers are needed to improve the sensitivity and accuracy of diagnosis, and also prognosis, in individuals with early Alzheimer disease (AD). Measures of brain structure and disease-related proteins in the cerebrospinal fluid (CSF) have been proposed as biomarkers, yet relatively little is known about the relationships between such measures. The present study was conducted to assess the relationship between CSF Aβ and tau protein levels and longitudinal measures of hippocampal structure in individuals with and without very mild dementia of the Alzheimer type.

DESIGN:

A single CSF sample and longitudinal magnetic resonance scans were collected. The CSF samples were assayed for tau, phosphorylated tau181 (p-tau181), Aβ1-42, and Aβ1-40 using an enzyme-linked immunosorbent assay. Large-deformation diffeomorphic metric mapping was used to generate hippocampal surfaces, and a composite hippocampal surface (previously constructed from 86 healthy participants) was used as a structural reference.

PATIENTS OR OTHER PARTICIPANTS:

Thirteen participants with very mild AD (Clinical Dementia Rating, CDR 0.5) and 11 cognitively normal participants (CDR 0).

INTERVENTION:

None.

MAIN OUTCOME MEASURES:

Initial and rate-of-change measures of total hippocampal volume and displacement of the hippocampal surface within zones overlying the CA1, subiculum, and CA2-4+DG cellular subfields, and their correlations with initial CSF measures.

RESULTS:

Lower CSF Αβ1-42 levels and higher tau/Αβ1-42 and p-tau181/Αβ1-42 ratios were strongly correlated with decreases in hippocampal volume and measures of progressive inward deformations of the CA1 subfield in participants with early AD, but not in cognitively normal participants.

CONCLUSIONS:

Despite the small sample size, we found that Αβ1-42 related and tau-related CSF measures were associated with hippocampal degeneration in individuals with clinically diagnosed early AD and may reflect an association with a common underlying disease mechanism.

PMID:
22156755
[PubMed - as supplied by publisher]
13.
Rev Neurol (Paris). 2011 Dec 8. [Epub ahead of print]

[Multicenter study on lumbar puncture indication, clinical practice and feasibility.]

[Article in French]

Source

CMRR Paris Nord Île-de-France, groupe hospitalier Lariboisière Fernand-Widal Saint-Louis, AP-HP, université Denis-Diderot, 2, rue Ambroise-Paré, 75010 Paris, France; Laboratoire de biologie du vieillissement, groupe hospitalier Lariboisière Fernand-Widal Saint-Louis, AP-HP, université Denis-Diderot, 2, rue Ambroise-Paré, 75010 Paris, France; Inserm U839, institut du Fer-à-Moulin, 17, rue du Fer-à-Moulin, 75005 Paris, France.

Abstract

INTRODUCTION:

Cerebrospinal fluid (CSF) biomarkers have been extensively studied as diagnostic markers for Alzheimer's disease (AD). However, results are variable probably due to lumbar puncture (LP) procedure, CSF collection and transport. This intercenter variability highlights the need for an efficient standardization of clinical and technical procedures. The aims of this study were firstly to compare the LP procedure and CSF transport process in all French Memory Centers and secondly to evaluate the incidence of LP side effects in 100 patients with cognitive disturbances.

METHODS:

LP practice and side effect prospective questionnaires were sent to all French Memory Centers in May 2010. Memory Centers were asked about their LP procedure. The prospective study over a three-week-period has evaluated the LP feasibility and side effects. All data were collected until the end of July 2010.

RESULTS:

The answers of 18 out of 26 Memory Centers were collected. Although, these centers did not have the same LP procedure and CSF transport, the majority of them proceeded according to Innogenetics's advices concerning the use of polypropylene tubes and transport duration but not sample conditioning. Polypropylene tubes were different from one center to the other. CSF volume, pharmacological premedication and prevention of post-LP syndrome were variable in all responding centers. The prospective study carried out in 100 patients revealed a very good LP acceptability (93/100 patients). LP feasibility was 97 % (90/93) and failed LP were consequently performed with success using radiological scopes. Three minor complications were observed.

DISCUSSION AND CONCLUSION:

All French Centers complied with Innogenetics' recommendations for pretechnical CSF procedures; however each Center put in place its own procedure that was different one center to the other. It will be very interesting to compare cut-off and result values for Aβ, tau and phosphorylated tau protein on threonine 181 between several centers that used their own procedures. Acceptability and safety were very good in our short but significant prospective study. These results confirm the data of Zetterberg et al., 2010.

Copyright © 2011 Elsevier Masson SAS. All rights reserved.

PMID:
22153704
[PubMed - as supplied by publisher]
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14.
Rev Esp Geriatr Gerontol. 2011 Oct;46 Suppl 1:39-41.

[Role of biomarkers in the early diagnosis of Alzheimer's disease].

[Article in Spanish]

Source

Unidad de Alzheimer y Otros Trastornos Cognitivos, Servicio de Neurología, ICN, Hospital Clínic de Barcelona, Barcelona, España.

Abstract

Alheimer's disease is the most frequent cause of cognitive decline and behavioral abnormalities in adults. Diagnosis is currently made in the advanced phases. An an early diagnosis in the prodromal phase (or earlier if possible) is required for the prevention of this disease, its early management and the development of potential therapies that could alter its natural course. The syndromic concept of mild cognitive impairment (the presence of detectable and quantifiable deterioration in one of the cognitive domains but without affecting -or without substantially affecting- autonomic performance of instrumental function) and its variants has aided understanding of the predementia stages of Alheimer's disease, even though its etiology may involve multiple factors. The use of biomarkers such as determination of the proteins involved in the disease in cerebrospinal fluid (Aβ42-amyloid, total and phosphorylated tau) and measurement of the hippocampus and entorhinal cortex with magnetic resonance imaging and positron emission tomography (both glucose and amyloid measurements), alone or combined, could allow early and etiologic diagnosis. Patients with Alzheimer's disease show reduced Aβ42-amyloid levels and increased total and phosphorylated tau levels in cerebrospinal fluid.

Copyright © 2011 SEGG. Published by Elsevier Espana. All rights reserved.

PMID:
22152914
[PubMed - in process]
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15.
Int J Alzheimers Dis. 2011;2011:739847. Epub 2011 Nov 24.

Evidence for Elevated Cerebrospinal Fluid ERK1/2 Levels in Alzheimer Dementia.

Source

Department of Psychiatry and Psychotherapy, Laboratory for Molecular Neurobiology, LVR-Klinikum Essen, University of Duisburg-Essen, Virchowstraße 174, 45147 Essen, Germany.

Abstract

Cerebrospinal fluid (CSF) samples from 33 patients with Alzheimer dementia (AD), 21 patients with mild cognitive impairment who converted to AD during followup (MCI-AD), 25 patients with stable mild cognitive impairment (MCI-stable), and 16 nondemented subjects (ND) were analyzed with a chemiluminescence immunoassay to assess the levels of the mitogen-activated protein kinase ERK1/2 (extracellular signal-regulated kinase 1/2). The results were evaluated in relation to total Tau (tTau), phosphorylated Tau (pTau), and beta-amyloid 42 peptide (Aβ42). CSF-ERK1/2 was significantly increased in the AD group as compared to stable MCI patients and the ND group. Western blot analysis of a pooled cerebrospinal fluid sample revealed that both isoforms, ERK1 and ERK2, and low amounts of doubly phosphorylated ERK2 were detectable. As a predictive diagnostic AD biomarker, CSF-ERK1/2 was inferior to tTau, pTau, and Aβ42.

PMID:
22145083
[PubMed - in process]
PMCID: PMC3227514
Free PMC Article
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16.
Neurobiol Aging. 2011 Dec;32 Suppl 1:S4-9.

CSF biomarkers for Alzheimer's disease: current utility and potential future use.

Source

Department of Neurology, Developmental Biology, Knight Alzheimer's Disease Research Center, and the Hope Center for Neurological Disorders, Washington University, St Louis, MO 63110, USA. holtzman@neuro.wustl.edu

Abstract

Over the past 15 years, cerebrospinal fluid (CSF) biomarkers have been shown to be useful for both the diagnosis as well as the prognosis in Alzheimer's disease. It has been shown the CSF levels of amyloid-β (Aβ)(42) are a very good marker for the presence of amyloid deposition in the brain regardless of clinical status and that total tau andphosphorylated forms of tau are useful in detection of neurodegeneration. When combined together, these CSF markers are useful not only in differential diagnosis but also in predicting conversion and rate of progression from mild cognitive impairment/very mild dementia to more severe impairment. The markers are also useful in predicting conversion from cognitive normalcy to very mild dementia. This field is briefly reviewed and recommendations for future studies in this area are provided.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
22078172
[PubMed - in process]
PMCID: PMC3233690
[Available on 2012/12/1]
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17.
Med Hypotheses. 2012 Feb;78(2):293-8. Epub 2011 Dec 2.

Dietary intake of cottonseed toxins is hypothesized to be a partial cause of Alzheimer's disorder.

Source

Wisconsin Institute of Nutrition, 6789 N. Green Bay Ave., Milwaukee, WI 53209, United States.

Abstract

The cause of Alzheimer's disorder is not known. The most influential known risk factor is increasing age. The risk factor of increasing age is consistent with exposure to environmental toxins throughout life as a cause of Alzheimer's. In addition, microbleeding, changes in membrane permeability and increased cholesterol are all factors important in Alzheimer's. Cottonseed contains toxins and is fed to animals, fish and poultry. Cottonseed toxins remain in the animals, fish and poultry and are present in the human diet at seemingly low levels. The average person is ingesting cottonseed toxins throughout life. Cottonseed toxins cause bleeding, changes in membrane permeability and increased cholesterol. In addition, the cottonseed toxin gossypol is known to reach the brain and bind randomly to important cellular structures. Gossypol also binds to microtubules and interferes with microtubule assembly, which may inhibit binding of tau to microtubules and lead to formation of neurofibrillary tangles. Cottonseed toxins are also known to accumulate in the body. In a preliminary study of female rats fed low level cottonseed for their lifetimes, apparent neurofibrillary tangles and phosphorylated tau were found. The intake of cottonseed toxins throughout life should be evaluated further as a possible cause of Alzheimer's.

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID:
22136946
[PubMed - in process]
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18.
Neurobiol Aging. 2011 Nov 29. [Epub ahead of print]

Pitavastatin decreases tau levels via the inactivation of Rho/ROCK.

Source

Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.

Abstract

Epidemiological studies have shown that long-term treatment with statins decreases the risk of developing Alzheimer's disease. Statins have pleiotropic effects by lowering the concentration of isoprenoid intermediates. Although several studies have shown that statins may reduce amyloid beta protein levels, there have been few reports on the interaction between statins and tau. We report here that pitavastatin reduces total and phosphorylated tau levels in a cellular model of tauopathy, and in primary neuronal cultures. The decrease caused by pitavastatin is reversed by the addition of mevalonate, or geranylgeranyl pyrophosphate. The maturation of small G proteins, including RhoA was disrupted by pitavastatin, as was the activity of glycogen synthase kinase 3β (GSK3β), a major tau kinase. Toxin A, inhibitor of glycosylation of small G proteins, and Rho kinase (ROCK) inhibitor decreased phosphorylated tau levels. Rho kinase inhibitor also inactivated glycogen synthase kinase 3β. Although the mechanisms responsible for the reduction in tauprotein by pitavastatin require further examination, this report sheds light on possible therapeutic approaches to tauopathy.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID:
22133277
[PubMed - as supplied by publisher]
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19.
Eur J Pharmacol. 2012 Jan 15;674(2-3):280-6. Epub 2011 Nov 12.

(Val(8)) glucagon-like peptide-1 prevents tau hyperphosphorylation, impairment of spatial learning and ultra-structural cellular damage induced by streptozotocin in rat brains.

Source

Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, PR China.

Abstract

It has being shown that glucagon-like peptide-1 (GLP-1), a new anti-diabetes agent, significantly attenuated beta-amyloid (Aβ) levels in rats. In the present study, (Val(8))GLP-1 was used to prevent impairments in memory formation,tau hyperphosphorylation and ultra-structural changes induced by streptozotocin intracerebroventricular (i.c.v.) injection. A spatial water maze task was used to test the rats' learning and memory formation, Western blot was used to measuretau hyperphosphorylation/total tau, and transmission electron microscope was used to find ultra-structural changes. The results shown that streptozotocin induced a series of Alzheimer disease -like changes in behaviour, a significant decline in learning and memory formation, an increased expression of total tau and an increased ratio of phosphorylated tau, and damage to nucleus and nucleolus as seen in electron micrographs. After treatment with (Val(8))GLP-1 (50μM in 10μl i.c.v.), there is a significant improvement in learning and memory, a reduction in total tau expression and hyperphosphorylated tau levels, and a recovery of damaged cell nuclei and nucleolus. Our results indicated that (Val(8))GLP-1 might prevent age-related neurodegenerative changes by preventing decline of learning and memory formation, reduction of phosphorylated tau levels and protection of subcellular structures and morphology of neurons. Therefore, (Val(8))GLP-1 is potentially a novel treatment for Alzheimer's disease.

Copyright © 2011 Elsevier B.V. All rights reserved.

PMID:
22115895
[PubMed - in process]
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20.
J Pathol. 2011 Nov 21. doi: 10.1002/path.3969. [Epub ahead of print]

The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies.

Source

Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Abstract

The unfolded protein response (UPR) is a stress response activated upon disturbed homeostasis in the endoplasmic reticulum (ER). Previously, we reported that the activation of the UPR closely correlates with the presence ofphosphorylated tau (p-tau) in Alzheimer's disease (AD). As well as increased presence of intracellular p-tau, AD brains are characterized by extracellular deposits of β amyloid (Aβ). Recent in vitro studies have shown that Aβ can induce ER stress and activation of the UPR. The aim of the present study is to investigate UPR activation in sporadic tauopathies like progressive supranuclear palsy (PSP) and Pick's disease (PiD), and familial cases with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) which carry mutations in the gene encoding for tau (MAPT). The presence of phosphorylated pancreatic ER kinase (pPERK) and phosphorylated inositol requiring enzyme 1α (pIRE1), which are indicative for an activated UPR, was assessed by immunohistochemistry in cases neuropathologically defined as frontotemporal lobar degeneration with tau inclusion (FTLD-tau). Increased presence of UPR activation markers pPERK and pIRE1 were observed in neurons and glia in FTLD-tau cases, in contrast to FTLD subtypes negative for tauinclusions or in non-neurological controls. pPERK and pIRE1 were also prominently present in relatively young carriers of MAPT mutation. A strong association between the presence of UPR activation markers and p-tau was observed in the hippocampus of FTLD-tau cases. Double immunohistochemical staining on FTLD-tau cases revealed that UPR activation is predominantly observed in neurons that show a diffuse staining of p-tau. These data demonstrate that UPR activation is intimately connected with the accumulation and aggregation of p-tau, and occurs independently from Aβ deposits. Our findings provide new pathological insight in the close association between p-tau and UPR activation in tauopathies. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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