Alzheimer’s
Frontotemporal
lobar degeneration(FTLD)
2009/7/22
J
Alzheimers Dis. 2009 Mar;16(3):601-7. 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. 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. 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. 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. 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. 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
CSF biomarkers in Alzheimer's disease and controls: associations
with APOE genotype are modified by age.
A distinct clinical, neuropsychological and radiological phenotype
is associated with progranulin gene mutations in a large UK series.
Cerebrospinal fluid beta-amyloid1-42 and tau in control subjectsat
risk for Alzheimer's disease: the effect of APOE epsilon4 allele.
Associationbetween the
extended tau haplotype and frontotemporal dementia.
Increased risk for frontotemporal dementia through
interactionbetween tau polymorphisms and apolipoprotein E epsilon4.
.