Flowchart: Preparation: Tau

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Alzheimer’s

Text Box: Tau

Frontotemporal lobar degeneration(FTLD)                                                        

 

Text Box: Apoe
 


2009/7/22

J Alzheimers Dis. 2009 Mar;16(3):601-7.Click here to read Links

CSF biomarkers in Alzheimer's disease and controls: associations with APOE genotype are modified by age.

Kester MI, Blankenstein MA, Bouwman FH, van Elk EJ, Scheltens P, van der Flier WM.

Alzheimer Center and Department of Neurology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands. m.kester@vumc.nl

 

The object of this study was to elucidate the effect of age in the relationship between APOE genotype and CSF biomarkers amyloid-beta1-42 (Abeta42), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) in AD and controls. 302 AD patients and 174 controls were categorized into APOE epsilon4 carriers and non-carriers, and into younger and older (65years). In controls, older age and APOE epsilon4 were independently associated with lower Abeta42 and higher tau and ptau-181 levels (p < 0.05). For tau and ptau-181, there were also interactions (p < 0.10): older carriers had higher levels than older non-carriers, without effect for younger controls. In AD, APOE epsilon4 genotype had a main effect on Abeta42, but there was also an interaction: older carriers had lower Abeta42 than older non-carriers, without effect for younger AD patients (p < 0.05). For tau and ptau-181, there were only interactions: older carriers had higher levels than older non-carriers, while younger AD patients showed the opposite (p 0.05). Association between CSF biomarkers and APOE genotype were modified by age in both controls and AD patients. This suggests that cognitively healthy APOE epsilon4 carriers are more prone to develop AD pathology with aging. For AD patients, this provides support for the existence of subtypes within the disease.

 

 

Brain. 2008 Mar;131(Pt 3):706-20. Epub 2008 Jan 29.Click here to read Click here to readLinks

A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series.

Beck J, Rohrer JD, Campbell T, Isaacs A, Morrison KE, Goodall EF, Warrington EK, Stevens J, Revesz T, Holton J, Al-Sarraj S, King A, Scahill R, Warren JD, Fox NC, Rossor MN, Collinge J, Mead S.

MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.

Mutations in the progranulin gene (GRN) are a major cause of frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) but the distinguishing clinical and anatomical features of this subgroup remain unclear. In a large UK cohort we found five different frameshift and premature termination mutations likely to be causative of FTLD in 25 affected family members. A previously described 4-bp insertion mutation in GRN exon 2 comprised the majority of cases in our cohort (20/25), with four novel mutations being identified in the other five affected members. Additional novel missense changes were discovered, of uncertain pathogenicity, but deletion of the entire gene was not detected. The patient collection was investigated by a single tertiary referral centre and is enriched for familial early onset FTLD with a high proportion of patients undergoing neuropsychological testing, MRI and eventual neuropathological diagnosis. Age at onset was variable, but four mutation carriers presented in their 40s and when analysed as a group, the mean age at onset of disease in GRN mutation carriers was later than tau gene (MAPT) mutation carriers and duration of disease was shorter when compared with both MAPT and FTLD-U without mutation. The most common clinical presentation seen in GRN mutation carriers was behavioural variant FTLD with apathy as the dominant feature. However, many patients had language output impairment that was either a progressive non-fluent aphasia or decreased speech output consistent with a dynamic aphasia. Neurological and neuropsychological examination also suggests that parietal lobe dysfunction is a characteristic feature of GRN mutation and differentiates this group from other patients with FTLD. MR imaging showed evidence of strikingly asymmetrical atrophy with the frontal, temporal and parietal lobes all affected. Both right- and left-sided predominant atrophy was seen even within the same family. As a group, the GRN carriers showed more asymmetry than in other FTLD groups. All pathologically investigated cases showed extensive type 3 TDP-43-positive pathology, including frequent neuronal cytoplasmic inclusions, dystrophic neurites in both grey and white matter and also neuronal intranuclear inclusions. Finally, we confirmed a modifying effect of APOE-E4 genotype on clinical phenotype with a later onset in the GRN carriers suggesting that this gene has distinct phenotypic effects in different neurodegenerative diseases.

PMID: 18234697 [PubMed - indexed for MEDLINE]

Neurosci Lett.2008 Aug 1;440(2):145-9. Epub2008 May 24.Click here to readLinks

CSF beta-amyloid 1-42 and tau in Tunisian patients withAlzheimer's disease: the effect of APOE epsilon4 allele.

SmachMA,CharfeddineB,LammouchiT,HarrabiI,BenOthman L,DridiH,BennamouS,LimemK.

Department of Biochemistry, Faculty of Medicine ofSousse, Tunisia. dalifms@yahoo.fr

 

Alzheimer's disease (AD) is theleading cause of dementia. Currently, no definitive diagnostic test for ADexists. An accurate, convenient and objective test to detect AD is urgentlyneeded for efficient drug development and effective clinical use ofemerging therapies. The aim of the present work is to investigate theusefulness of cerebrospinal fluid (CSF) beta-amyloid protein (Abeta1-42)and total tau protein (t-tau) analyses in the diagnosis of AD and whetherapolipoprotein E (ApoE) epsilon4 allele is a factor for AD affectingTunisian people. Abeta1-42 and t-tau levels were measured in CSF from ADpatients (n=73), non-Alzheimer dementia (nAD, n=35) and healthy controls(HC, n=38) by sandwich enzyme-linked immunosorbent assay. Abeta1-42 levelswere decreased and t-tau increased in AD patients. The combination ofAbeta1-42 and t-tau at baseline yielded a sensitivity of 87.4% fordetection of AD. The specificities were 97.3% for controls and 82.7% forother dementia. The ApoE epsilon4 allele frequency (29.5%) wassignificantly higher in the AD patients than in the nAD patients (17.1%) orin the control groups (9.5%). AD patients carrying ApoE epsilon4 allele hadlower Abeta1-42 (p<0.001) levels than those without a epsilon4 allele.The combination of t-tau and Abeta1-42 is a robust and reliable assay thatmay be useful in discriminating cases at risk for AD such as ApoE epsilon4allele carriers from nAD patients or from age-matched control subjects

BiolPsychiatry.2004 Nov 1;56(9):670-6.Click here to readLinks

Cerebrospinal fluid beta-amyloid1-42 and tau in control subjectsat risk for Alzheimer's disease: the effect of APOE epsilon4 allele.

SunderlandT,MirzaN,PutnamKT,LinkerG,BhupaliD,DurhamR,SoaresH,KimmelL,FriedmanD,BergesonJ,CsakoG,LevyJA,BartkoJJ,CohenRM.

National Instituteof Mental Health, GeriatricPsychiatry Branch, Building 10, Room 3N228, 9000 Rockville Pike, Bethesda,MD 20892, USA. trey@mail.nih.gov

 

BACKGROUND: Cerebrospinal fluid (CSF) measures ofbeta-amyloid(1-42) and tau are linked with the known neuropathology ofAlzheimer's disease (AD). Numerous lines of evidence have also suggestedthat individuals with at least one APOE epsilon4 allele on chromosome 19are at increased risk of developing AD. We tested these CSF markers ingroups of subjects with AD and healthy older control subjects, using theabsence or presence of the APOE epsilon4 allele as a predictive variable inthe search for possible prognostic biomarkers of AD. METHODS: We assessedthe levels of beta-amyloid(1-42) and total tau in the CSF of 292 subjects(142 control subjects and 150 subjects with mild-to-moderate AD), who wereresearch participants at the National Institute of Mental Health. The groupof control subjects was enriched with a high percentage of subjects with apositive family history of AD. All subjects underwent extensive global cognitivetesting. RESULTS: When divided according to the absence or presence of theAPOE epsilon4 allele, the control subjects with at least one epsilon4allele had significantly lower CSF beta-amyloid(1-42) but not tau levelsthan control subjects without an APOE epsilon4 allele (p<.01). Asexpected, the AD patients had lower levels of CSF beta-amyloid(1-42) andhigher CSF tau levels than the normal control group (p<.01).CONCLUSIONS: The association of APOE epsilon4 allele and lower, moreAD-like levels of CSF beta-amyloid(1-42) in older control subjects isconsistent with previous studies showing possible neuroimaging andcognitive abnormalities with epsilon4 carriers and suggests that CSFbeta-amyloid(1-42) decreases might represent an early biomarker of AD.Longitudinal follow-up is of course required to verify whether thisbiomarker is indeed predictive of clinical conversion to AD.

 

Arch Neurol.2002 Jun;59(6):935-9.Click here to readLinksAssociationbetween the extended tau haplotype and frontotemporal dementia.

VerpillatP,CamuzatA,HannequinD,Thomas-AnterionC,PuelM,BelliardS,DuboisB,DidicM,MichelBF,LacomblezL,MoreaudO,SellalF,GolfierV,CampionD,Clerget-DarpouxF,BriceA.

Département d'Epidémiologie, de Biostatistique, et deRecherche Clinique, Hôpital Bichat-Claude Bernard, 46 rue Henri Huchard, 75877Paris CEDEX 18, France. patrice.verpillat@bch.ap-hop-paris.fr

 

BACKGROUND: Recent studies have shown an associationbetween an extended tau haplotype (H1) that covers the entire human tau geneand progressive supranuclear palsy or, more inconsistently, otherneurodegenerative disorders, such as corticobasal degeneration, Parkinsondisease, Alzheimer disease, and frontotemporal dementia (FTD). In addition,disease-causing mutations in the tau gene on chromosome 17 have beendetected in some families with autosomal dominant FTD and parkinsonism. InFTD, the pathological accumulation of the microtubule-associated proteintau suggests that the tau gene may be a genetic risk factor for this disorder.OBJECTIVE: To confirm or refute the association between the H1 haplotype orthe H1H1 genotype of the tau gene and FTD. DESIGN: Case-control study.SETTING: Neurology departments of 12 French university hospitals.PARTICIPANTS: One hundred unrelated patients with FTD and 79 controls.METHODS: Tau genotype (contiguous polymorphisms in exons 1, 7, and 13 andin intron 9 used to reconstruct the extended haplotypes H1 and H2).Clinical examination, psychometric testing, laboratory tests, computedtomography and magnetic resonance imaging, single-photon emission computedtomography, and electroencephalography for patients with FTD. RESULTS: TheH1H1 genotype was significantly overrepresented in patients with FTDcompared with controls (62% vs 46%; P=.01, 1-sided; odds ratio adjusted forage and sex, 1.95). After stratification according to apolipoprotein E(APOE) genotype, we found a significant interaction between APOE and taugenotypes (P=.03). CONCLUSIONS: This study of the largest series ofpatients with FTD confirms the primary role of tau in FTD and establishesthat the H1 haplotype of the tau gene and the E2 allele of APOE interact byan unknown mechanism that increases the risk of FTD

 

Neuroreport.2001 Apr 17;12(5):905-9.Click here to readLinks

Increased risk for frontotemporal dementia through interactionbetween tau polymorphisms and apolipoprotein E epsilon4.

IngelsonM,FabreSF,LiliusL,AndersenC,ViitanenM,AlmkvistO,WahlundLO,LannfeltL.

Karolinska Institutet, NEUROTEC, Novum, KFC, Huddinge,Sweden.

 

The tau gene has an important role in frontotemporaldementia (FTD) as pathogenic mutations have been found in hereditary formsof the disease. Furthermore, a certain extended tau haplotype has beenshown to increase the risk for progressive supranuclear palsy, corticobasaldegeneration, Parkinson's disease and, in interaction with theapolipoprotein E (apoE) epsilon4 allele, Alzheimer's disease. Bymicrosatellite analysis we investigated an intronic tau polymorphism, inlinkage disequilibrium with the extended tau haplotype, in FTD patients (n= 36) and healthy controls (n = 39). No association between any of the taualleles/genotypes and FTD was seen, but certain tau alleles and apoEepsilon4 interactively increased the risk of FTD (p = 0.006). We thuspropose that this extended tau haplotype in combination with apoE epsilon4is a genetic risk factor for

 

 

            

 

 
 


 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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