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M. C. ROYSTON, D. MANN,
S. PICKERING-BROWN,
F. OWEN,
R. PERRY,
R. RAGBHAVAN,
C. KHIN-NU,
S. TYNER,
K. DAY,
R. CROOK,
J. HARDY,
G. W. ROBERTS
[show abstract]
[hide abstract]
ABSTRACT: All individuals with Down's syndrome (trisomy 21-DS) develop the pathogenic hallmarks of Alzheimer's disease in old age (+40 years).1-4 The extent of pathology is variable, but it has been shown that the amount of β-amyloid pathology is variable and related to age and the degree of dementia.3 Thus, in DS, growing old is associated with a progressive pathological process which results in cognitive decline. However, neuropsychological studies of older DS subjects have identified a clinical dementia in only a proportion of cases.1-4These contradictory observations could be reconciled if some factor existed which modulated the rate and amount of β-amyloid pathology. Recent studies demonstrate an association between the apolipoprotein E4 (ApoE4) allele and the earlier age of onset in both sporadic8-9 and familial10 AD. Increased amounts of βamyloid pathology can also be related to the E4 allele. However, at present there are no data documenting the effects of ApoE genotype on the expression or degree of clinical symptoms of the disease. We have examined the ApoE genotype in a cohort of clinically evaluated elderly patients with DS in order to examine the effects of ApoE genotype on the clinical symptoms of dementia. We report here that, despite the presence of an active disease process, the ApoE E2 allele is associated with longevity and preservation of cognitive functioning.
Annals of the New York Academy of Sciences 12/2006; 777(1):255 - 259. · 3.15 Impact Factor
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H Houlden,
M Baker,
H R Morris,
N MacDonald,
S Pickering-Brown,
J Adamson,
A J Lees,
M N Rossor,
N P Quinn,
A Kertesz, [......],
D G Munoz, D Mann,
A E Lang,
C Bergeron,
E H Bigio,
I Litvan,
K P Bhatia,
D Dickson,
N W Wood,
M Hutton
[show abstract]
[hide abstract]
ABSTRACT: To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD).
The authors previously described an extended tau haplotype (H1) that covers the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD.
The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls.
Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X(2) = 9.1, p = 0.00255 [1df], OR 3.56 [8.43 > CI 95% > 1.53]). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X(2) = 17.42, p = 0.00016, 2df), OR 3.61 [7.05 > CI 95% > 1.85]).
The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.
Neurology 06/2001; 56(12):1702-6. · 8.31 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: It is unclear whether the APOE epsilon4 allele is associated with distinct clinical features in dementia.
100 cases meeting ICD criteria for dementia were interviewed using standardized instruments and genotyped for APOE. The presence of the epsilon4 allele was used by a genetic algorithm neural network (GANN) to discriminate symptoms and signs.
The GANN selected six features: gender, systolic blood pressure, absence of ankle tendon reflexes, history of weight loss, history of falls, and interviewer observed lability of mood. Using these features, a neural network discriminated cases according to epsilon4 highly accurately (area under receiver operating characteristic=0.83, sensitivity=0.78, specificity=0.78).
A GANN is able to discriminate a clinically distinct group of features among dementia patients who express the epsilon4 allele.
International Journal of Geriatric Psychiatry 02/2001; 16(1):77-81. · 2.42 Impact Factor
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S Pickering-Brown,
M Baker,
S H Yen,
W K Liu,
M Hasegawa,
N Cairns,
P L Lantos,
M Rossor,
T Iwatsubo,
Y Davies,
D Allsop,
R Furlong,
F Owen,
J Hardy, D Mann,
M Hutton
[show abstract]
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ABSTRACT: Recently, mutations within the tau gene have been associated with some familial forms of frontotemporal dementia. To investigate whether tau gene mutations are also associated with Pick's disease, we analyzed the tau gene in 30 cases of pathologically confirmed Pick's disease. Two coding mutations were identified in separate cases of Pick's disease. A glycine-to-arginine mutation at codon 389 was detected in 1 case and a lysine-to-threonine mutation at codon 257 was identified in another. Analysis of dephosphorylated tau from the brain of the patient with the codon 389 mutation revealed a prominent band representing tau, with four microtubule-binding domains and no amino terminal inserts. This is in contrast to Pick's disease without any tau gene mutations, which consist of tau with mainly three microtubule-binding domains and only a trace of tau, with four microtubule-binding domains. Functional analysis of tau with these two mutations demonstrated a reduced ability of tau to promote microtubule assembly. Surprisingly, these mutations increased tau's susceptibility to calpain I digestion, suggesting that this feature may be related to the formation of a Pick type of histology. Moreover, these data suggest that Pick's disease is not a separate entity but part of the frontotemporal dementia disease spectrum.
Annals of Neurology 01/2001; 48(6):859-67. · 11.09 Impact Factor
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H Houlden,
M Baker,
J Adamson,
A Grover,
S Waring,
D Dickson,
T Lynch,
B Boeve,
R C Petersen,
S Pickering-Brown,
F Owen,
D Neary,
D Craufurd,
J Snowden, D Mann,
M Hutton
[show abstract]
[hide abstract]
ABSTRACT: Splice-site and missense mutations have been identified in tau associated with frontotemporal dementia with parkinsonism linked to chromosome 17. In this study we assessed the genetic contribution of tau mutations to three patient series with non-Alzheimer's (non-AD) degenerative dementia. The groups included (1) a community-based dementia series from Minnesota, MN; (2) a referral series with clinicopathological tauopathy; and (3) a pathologically confirmed familial frontotemporal dementia series from Manchester, UK. Comparing the three clinical series: in the stringently diagnosed Manchester frontotemporal dementia series, tau mutations were present in 13.6% of cases (three splice-site mutations); in the clinicopathological referral series that used more general inclusion criteria, 3 cases with P301L mutations were observed, which represents a lower mutation frequency of 3.6% (9.4% in familial cases); in contrast, tau mutations were not detected in the Minnesota community-based dementia series, suggesting the occurrence of these mutations in dementia generally is rare (<0.2%). These data identify the prevalence of mutations in three different clinical settings and indicate that this figure is sensitive to the diagnostic criteria used in each patient series.
Annals of Neurology 09/1999; 46(2):243-8. · 11.09 Impact Factor
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H Houlden,
P Rizzu,
M Stevens,
P de Knijff,
C M van Duijn,
J C van Swieten,
P Heutink,
J Perez-Tur,
V Thomas,
M Baker, [......],
F Dark,
B Boeve,
D Dickson,
P Davies,
S Pickering-Brown, D Mann,
J Adamson,
T Lynch,
H Payami,
J Hardy
[show abstract]
[hide abstract]
ABSTRACT: We have assessed whether apolipoprotein E (ApoE) genotype influences the age of onset of dementia in a series of families with frontal temporal dementia with defined mutations in the tau gene. In contrast to the situation in Alzheimer's disease (AD), we could find no evidence that the age of onset of disease was influenced by the ApoE genotype.
Neuroscience Letters 03/1999; 260(3):193-5. · 2.11 Impact Factor
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M Hutton,
C L Lendon,
P Rizzu,
M Baker,
S Froelich,
H Houlden,
S Pickering-Brown,
S Chakraverty,
A Isaacs,
A Grover, [......],
D Craufurd,
D Neary,
F Owen,
B A Oostra,
J Hardy,
A Goate,
J van Swieten, D Mann,
T Lynch,
P Heutink
[show abstract]
[hide abstract]
ABSTRACT: Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10. This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.
Nature 07/1998; 393(6686):702-5. · 36.28 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The aims of this study were (a) to determine the frequency of APOE genotypes in dementia, (b) to relate e4 allele frequency to clinical symptomatology of dementia and (c) to relate e4 and assess risk factors for different types of dementia.
Prospective clinical study setting older patients with dementia known to a community-based old age psychiatry service.
101 patients fulfilling ICD 10 criteria for dementia.
Replication of previous findings of an association between APOE4 and Alzheimer's disease: younger age of onset of dementia; family history of dementia; persecutory ideation; and (retrospectively determined) rate of competent decline. No association was found between APOE4 and vascular dementia. The association between APOE4 and 'mixed dementia' was intermediate between that of pure Alzheimer's disease and pure vascular dementia.
The results confirm the relationship between clinical features of dementia and APOE4 status. It may be that APOE can be used as an adjunct to clinical diagnosis.
International Journal of Geriatric Psychiatry 04/1998; 13(3):177-85. · 2.42 Impact Factor
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M C Royston, D Mann,
S Pickering-Brown,
F Owen,
R Perry,
R Ragbavan,
C Khin-Nu,
S Tyner,
K Day,
R Crook,
J Hardy,
G W Roberts
[show abstract]
[hide abstract]
ABSTRACT: All individuals with Down's syndrome (trisomy 21-DS) develop the pathogenic hallmarks of Alzheimer's disease in old age (+40 years). The extent of pathology is variable, but it has been shown that the amount of beta-amyloid pathology is variable and related to age and the degree of dementia. Thus, in DS, growing old is associated with a progressive pathological process which results in cognitive decline. However, neuropsychological studies of older DS subjects have identified a clinical dementia in only a proportion of cases. These contradictory observations could be reconciled if some factor existed which modulated the rate and amount of beta-amyloid pathology. Recent studies demonstrate an association between the apolipoprotein E4 (ApoE4) allele and the earlier age of onset in both sporadic and familial AD. Increased amounts of beta-amyloid pathology can also be related to the E4 allele. However, at present there are no data documenting the effects of ApoE genotype on the expression or degree of clinical symptoms of the disease. We have examined the ApoE genotype in a cohort of clinically evaluated elderly patients with DS in order to examine the effects of ApoE genotype on the clinical symptoms of dementia. We report here that, despite the presence of an active disease process, the ApoE E2 allele is associated with longevity and preservation of cognitive functioning.
Annals of the New York Academy of Sciences 02/1996; 777:255-9. · 3.15 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Although individuals with Down's syndrome nearly always develop the clinical and pathological features of Alzheimer's disease, some clearly do not become demented despite living into their sixth and seventh decades. Genetic variation at the apolipoprotein E locus has recently been shown to be an important determinant of Alzheimer's disease, with the epsilon 4 allele having been shown to be associated with the disease and, at least in some cases, the epsilon 2 allele being negatively associated with the disease. Here we show, in a series of clinically assessed individuals with Down's syndrome, that the epsilon 2 allele of ApoE is associated with both longevity and the absence of clinical evidence of dementia. These data show that the clinical phenotype of Down's syndrome can be modulated by genes on chromosomes other than chromosome 21. The importance of this observation to the pathogenesis of Alzheimer's disease, both in Down's syndrome and in general, is discussed.
Neuroreport 01/1995; 5(18):2583-5. · 1.66 Impact Factor
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H Houlden,
P Rizzu,
M Stevens,
P de Knijff,
C M van Duijn,
J C van Swieten,
P Heutink,
J Perez-Tur,
V. Thomas,
M Baker, [......],
J. C. Jannsen,
R C Petersen,
P. R. Dodd,
F Dark,
B Boeve,
D Dickson,
P Davies,
S Pickering-Brown, D Mann,
J Adamson
