Alzheimer disease PS-1 exon 9 deletion defined.
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Alzheimer Disease↗
Biomedical subjects
R Crook
Publications and source records attributed to R Crook.
Alpha-2 macroglobulin gene and Alzheimer disease.
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Aged↗
A chromosome 4p haplotype segregating with Parkinson's disease and postural tremor.
We investigated a large family with levodopa-responsive, Lewy body parkinsonism in which the disease segregates as an apparent autosomal dominant trait. After performing a genome screen, we identified a chromosome 4p haplotype that segregates with the disease. However, this haplotype also occurs in individuals in the pedigree who do not have clinical Lewy body parkinsonism but rather suffer from postural tremor, consistent with essential tremor. These data demonstrate a new locus for Lewy body parkinsonism and suggest that in some circumstances postural tremor can be an alternative phenotype of the samepathogenic mutation as Lewy body parkinsonism.
Chromosome Mapping↗
A full genome scan for late onset Alzheimer's disease.
We have genotyped 292 affected sibling pairs (ASPs) with Alzheimer's disease (AD) according to NINCDS-ADRDA diagnostic criteria and with onset ages of >/=65 years using 237 microsatellite markers separated by an average distance of 16.3 cM. Data were analysed by SPLINK and MAPMAKER/SIBS on the whole sample of 292 ASPs and subsets of 162 ASPs where both members possessed an apolipoprotein E (APOE)straightepsilon4 allele and 63 pairs where neither possessed anstraightepsilon4 allele. Sixteen peaks with a multipoint lod score (MLS) >1 either in the whole sample, the straightepsilon4-positive or -negative subgroups were observed on chromosomes 1 (two peaks), 2, 5, 6, 9 (two peaks), 10 (two peaks), 12, 13, 14, 19, 21 and X (two peaks). Simulation studies revealed that these findings exceeded those expected by chance, although many are likely to be false positives. The highest lod scores on chromosomes 1 (MLS 2.67), 9 (MLS 2.38), 10 (MLS 2.27) and 19 (MLS 1.79) fulfilLander and Kruglyak's definition of 'suggestive' in that they would be expected to occur by chance once or less per genome scan. Several other peaks were only marginally less significant than this, in particular those on chromosomes 14 (MLS 2.16), 5 (MLS 2.00), 12, close to alpha2-macroglobulin (MLS 1.91), and 21, close to amyloid precursor protein (MLS 1.77). This is the largest genome scan to date in AD and shows for the first time that this is a genetically complex disorder involving several, perhaps many, genes in addition to APOE. Moreover, our data will be of interest to those hoping to identify positional candidate genes using information emerging from neurobiological studies of AD.
Age of Onset↗
Genetic association of alpha2-macroglobulin with Alzheimer's disease in a Finnish elderly population.
Recently, two studies have reported an association between the alpha2-macroglobulin gene on chromosome 12 and late-onset Alzheimer's disease, whereas others have not been able to replicate these findings. By using a prospective population-based study, we have investigated the relation between two polymorphisms in this gene with the presence of the disease and also with the extent of pathological changes in the cerebral cortex. The Vantaa 85+ Study includes all 601 persons, at least 85 years of age, who were living in Vantaa, Finland, on April 1, 1991. The neocortical beta-amyloid protein load and the number of neurofibrillary tangles were determined on tissue sections by using methenamine silver staining and a modified Bielschowsky staining, respectively. The A/A genotype in exon 24 of the alpha2-macroglobulin gene was associated with neuropathologically defined diagnosis of Alzheimer's disease according to the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) criteria and with an increase in the neocortical beta-amyloid protein load. The effect of this association was stronger in the apolipoprotein E epsilon4-negative group. Therefore, genetic variability in the alpha2-macroglobulin gene is a risk factor associated with neuropathologically defined Alzheimer's disease in our population, as well as with the extent of neocortical beta-amyloid protein deposition.
Adult↗
Genetic studies on chromosome 12 in late-onset Alzheimer disease.
CONTEXT: The only genetic locus universally accepted to be important as a risk factor for late-onset Alzheimer disease (AD) is the apolipoprotein E (APOE) locus on chromosome 19. However, this locus does not account for all the risk in late-onset disease, and a recent report has suggested a second locus on chromosome 12p11-12. OBJECTIVE: To look for evidence of linkage on chromosome 12 and to test for the presence of the new locus in an independent sample of familial late-onset AD cases. DESIGN: Retrospective cohort study. As part of a 20-centimorgan genome screen (approximately equal to 200 markers), we tested a series of 18 genetic markers on chromosome 12 and carried out multipoint, nonparametric lod score and exclusion analyses. SETTING: Clinic populations in the continental United States selected from the National Institute of Mental Health AD Genetics Consortium. PATIENTS: We selected samples for DNA analysis from affected sibling pairs, 497 subjects from 230 families with 2 or more affected individuals with probable or definite AD with onset ages older than 60 years (mean+/-SD, 75+/-6 years). Within the families, we used the 2 probable or definitely affected individuals. In families with more than 2 such cases available, we used all of them; in families with only 2 such cases in which unaffected individuals were available, we also sampled the oldest unaffected individual and used genotype data from this unaffected individual to check for nonpaternity and genotyping errors. MAIN OUTCOME MEASURE: Presence of linkage or locus on chromosome 12. RESULTS: Although linkage analyses confirmed the presence of a genetic susceptibility factor at the APOE locus in these families with late-onset AD, we were unable to confirm the presence of a locus close to the marker D12S1042. A moderate lod score (1.91) was found near D12S98 close to the alpha2-macroglobulin locus in the affected pairs in which both members did not possess an APOE epsilon4 allele. CONCLUSIONS: APOE remains the only locus established to be a risk factor for late-onset AD. We were unable to confirm that a locus on chromosome 12p11-12 has a major effect on risk for late-onset AD, although an effect smaller than that for APOE cannot be excluded.
Age of Onset↗
Exclusion of genetic linkage to 4q21-23 and 17q21 in a family with Lewy body parkinsonism.
Genetic analysis of markers from chromosomes 4q21-23 and 17q21 in a family with apparently autosomal dominant Lewy body parkinsonism is presented. This analysis shows that the locus leading to this disease is not allelic with that previously shown to lead to Lewy body parkinsonism on chromosome 4 or to the locus on chromosome 17 leading to frontotemporal dementia with parkinsonism. A brief clinical comparison of this family with families showing linkage to these loci is presented. The data suggest that at least one other major genetic determinant for Lewy body parkinsonism remains to be identified.
Adult↗
Exercise-induced changes in the QT interval duration and dispersion in patients with sudden cardiac death after myocardial infarction.
BACKGROUND: Prolongation of the QT interval and increased QT dispersion have been proposed to be associated with arrhythmic risk after myocardial infarction. However, controversy remains regarding the prognostic value of ventricular repolarization abnormalities in the risk stratification of patients surviving acute myocardial infarction. HYPOTHESIS AND OBJECTIVE: The QT interval is sensitive to myocardial ischaemia, and exercise-induced ischaemia may change the QT interval regionally, resulting in increased QT dispersion. This study examined whether there are abnormalities of ventricular repolarization during exercise and whether assessment of the exercise-induced changes in QT interval duration and dispersion would be able to differentiate patients at high risk from those at low risk of sudden cardiac death after myocardial infarction. METHODS: Twenty-six post-myocardial infarction patients (mean age 54.5+/-8.9 years, 22 men) were retrospectively studied. Thirteen patients who died suddenly (SCD patients) during a follow-up of 39+/-6 months were compared to 13 patients who remained event-free, i.e. no ventricular tachyarrhythmias, no reinfarction, no by-pass (MI survivors). The two groups were pair-matched for age, gender, site of infarction, left ventricular ejection fraction and use of beta blocker. A further 13 patients with chest pain, normal coronary arteriograms and negative exercise test results were studied as controls. They were age and gender matched with the post-infarction patients. A 12-lead exercise ECG was recorded from each patient before, during and after exercise. QT and RR interval were measured on the exercise ECGs at each stage and QT dispersion was defined as the difference between the maximum and minimum QT intervals across the 12-lead ECG. RESULTS: There were no significant differences in RR, QT and QTc (Bazett's and Fridericia's correction) intervals, or QT dispersion between any groups before exercise. A significant difference in QT and QT dispersion was found at peak exercise between post-infarction patients and controls (P=0.03 and P=0.0001, respectively), but no difference was observed between SCD patients and MI survivors. The maximum QTc at peak exercise was longer in SCD patients compared with MI survivors (P=0.02) and a maximum QTc>440 ms (Bazett's correction) was common in SCD patients but not in MI survivors or controls (62%, 15%, 15%, P=0.01). The differences in QT, QTc or QT dispersion observed at peak exercise were no longer significant after exercise. CONCLUSIONS: Exercise-induced prolongation of the QTc interval differentiates patients at high risk of sudden cardiac death from those at low risk, whereas exercise-induced changes in QT dispersion failed to identify patients at high risk of sudden cardiac death after myocardial infarction.
Adult↗
ApoE genotype is a risk factor in nonpresenilin early-onset Alzheimer's disease families.
The apolipoprotein E (ApoE) genotype is a significant risk factor and modulator of age of onset of Alzheimer's disease (AD). We analyzed the effect of the ApoE genotype in two distinct early-onset familial AD groups: families with a mutation in the presenilin-1 gene (PS-1) on chromosome 14, and families without a mutation detectable in the PS-1, presenilin-2 (PS-2), and the amyloid precursor protein (APP) gene (non-PS early-onset familial AD). The ApoE genotype is clearly shown not to modulate age of onset in families with a mutation in the PS-1 gene and families with no lesion detectable in either the presenilin or APP gene. The effects of a double dose of ApoE4 on age of onset were not assessed in the PS-1 AD families due to the lack of any affected ApoE4 homozygotes in the sample set; this insufficiency will need to be assessed in further studies. There was no association between the ApoE4 allele and AD in the PS-1 families. Non-PS early-onset AD families were shown to have a significantly higher frequency of ApoE4 compared to controls and the PS-1 AD group. These observations are important and suggest that 1) other genetic and environmental factors modify the AD phenotype in PS-1 and non-PS early-onset families; and 2) the ApoE4 allele is a significant risk factor in the etiology of non-PS early-onset AD and will be a useful adjunct in the diagnosis of unaffected family members.
Alleles↗
Low frequency of alpha-synuclein mutations in familial Parkinson's disease.
A mutation in exon 4 of the alpha-synuclein (NACP) gene has been reported to explain the chromosome 4 linkage to autosomal dominant Parkinson's disease. We developed primers and methods for exonic sequencing of this gene and sequenced the entire coding region of the gene in 6 families with autosomal dominant disease and in 2 cases of lytico and bodig from Guam. In addition, we have sequenced exon 4 of this gene in 5 cases of familial disease and have screened for the specific mutation (A53T) in a 40 cases of idiopathic Parkinson's disease, 3 cases of multisystem atrophy, and 15 cases of Lewy body dementia. We have found no genetic variation in the gene. We discuss these findings with respect to both the epidemiology of Parkinson's disease and the possibility that NACP is not the chromosome 4 locus for disease.
Adult↗
Elevated plasma lipoprotein(a) is associated with coronary artery disease in patients with chronic stable angina pectoris.
OBJECTIVES: We sought to assess the relation between plasma lipoprotein(a) [Lp(a)] levels, clinical variables and angiographic coronary artery disease (CAD) in patients with chronic stable angina. BACKGROUND: The relation between plasma Lp(a) levels and the severity and extent of angiographic CAD has not been studied in well characterized patients with stable angina pectoris. METHODS: We investigated clinical variables, lipid variables and angiographic scores in 129 consecutive white patients (43 women) undergoing coronary angiography for chronic stable angina. RESULTS: Plasma Lp(a) levels were significantly higher in patients with than in those without significant angiographic stenoses (> or =70%) (372 mg/liter [interquartile range 87 to 884] vs. 105 mg/liter [interquartile range 56 to 366], respectively, p=0.002). This difference remained significant when patients with mild or severe angiographic disease were compared with those with completely normal coronary arteries (312 mg/liter [interquartile range 64 to 864] vs. 116 mg/liter [interquartile range 63 to 366], respectively, p=0.02). However, subset analysis indicated that this difference achieved statistical significance only in women. Multiple logistic regression analysis indicated that Lp(a) concentration was independently predictive of significant angiographic stenoses (adjusted odds ratio [OR] 9.1, 95% confidence interval [CI] 2.0 to 42.1, p=0.006) and remained true even after exclusion of patients receiving lipid-lowering treatment (n=27) (OR 10.4, 95% CI 1.1 to 102.9, p=0.05). Lp(a) also had independent predictive value in a similar analysis using mild or severe angiographic disease as the outcome variable (OR 11.8, 95% CI 1.5 to 90.8, p=0.02). CONCLUSIONS: Our results indicate that elevated plasma Lp(a) is an independent risk factor for angiographic CAD in chronic stable angina and may have particular significance in women.
Aged↗
A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1.
We describe a novel variant of Alzheimer's disease (AD) in a Finnish pedigree with 17 affected individuals of both sexes in three generations. The disease is characterized by progressive dementia which is, in most cases, preceded by spastic paraparesis. Neuropathological investigations revealed numerous, distinct, large, round and eosinophilic plaques as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton wool balls and were immunoreactive for Abeta but lacked a congophilic dense core or marked plaque-related neuritic pathology. Molecular genetic analysis revealed that the disease was caused by a deletion of exon 9 (delta9) of the presenilin 1 (PS1) gene from the mRNA: unlike previous examples of the delta9 variant, the deletion was not caused by a splice acceptor site mutation.
Age of Onset↗
Computerised measurements of QT dispersion in healthy subjects.
OBJECTIVE: To assess the stability and reproducibility of computerised QT dispersion (QTd) measurement in healthy subjects, as this is presently being incorporated into commercial electrocardiographic systems. METHODS: 70 healthy volunteers (mean (SD) age 38 (10) years, 35 men, 35 women) with a normal 12 lead electrocardiogram (ECG) were studied. From each subject, 70 ECG recordings were taken using the MAC VU ECG recorder (Marquette). In study A, 50 ECGs were recorded in each subject: 10 supine, 10 sitting, 10 standing, 10 holding breath in maximum inspiration, and 10 holding breath in maximum expiration. After a mean interval of 8 (3) days (range 7 to 23), 10 recordings in supine and 10 in the standing position were repeated in each subject (study B). On measurements made using a research version of the commercial software without manual modification, the reproducibility of QTd was assessed by coefficient of variance (CV) and relative error, and comparisons made with other ECG indices. RESULTS: (1) QTd measurements were stable and not influenced by changes in posture and respiratory cycle; (2) there was no difference in QTd measurements between men and women, or between age groups dichotomised at 35 years; (3) no correlation was found between QTd and heart rate or QT interval; (4) short term reproducibility of all QTd measurements (CV 15.6% to 43.8%) was worse than that of conventional ECG indices (CV 1.4% to 5.3%); (5) long term reproducibility of QTd measurements (relative error 27.4% to 31.0%) was also worse than that of conventional ECG indices (relative error 1.8% to 7.9%) (p < 0.0001); (6) the reproducibility of QTd measurements tended to increase when several serial recordings were averaged. CONCLUSIONS: Computerised measurements of global QTd and global QT-SD from 12 lead ECG by the MAC VU/QT Guard system are not significantly altered by changes in posture and respiration. The reproducibility of all QTd measurements is inferior to that of conventional ECG indices in healthy subjects.
Adolescent↗
Early-onset Alzheimer's disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2 mutation.
We describe a new mutation causing Alzheimer's disease (AD) in presenilin-1 (N135D) that is at the homologous site to the presenilin 2 mutation (N141I) in Volga German kindreds. The phenotype of PS1 N135D is an early-onset (34-38 years) disease. The mutation forms part of, and extends, the alpha-helical array of mutations in transmembrane 2 of the presenilins and leads to the suggestion that disruption of this helical face is the molecular insult that leads to disease.
Adult↗
Localization of frontotemporal dementia with parkinsonism in an Australian kindred to chromosome 17q21-22.
An Australian family with autosomal dominant presenile nonspecific dementia was recently described. The disease results in behavioral changes, usually disinhibition, followed by the onset of dementia accompanied occasionally by parkinsonism. Twenty-eight affected individuals were identified with an age of onset of 39 to 66 years (mean, 53 +/- 8.9 years). We mapped the disease locus to an approximately 26-cM region of chromosome 17q21-22 with a maximum two-point LOD score of 2.87. Affected individuals share a common haplotype between markers D17S783 and D17S808. This region of chromosome 17 contains the loci for several neurodegenerative diseases that lack distinctive pathological features, suggesting that these dementias, collectively referred to as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), are caused by mutations in the same gene. The entire coding region of five genes, mapped to the FTDP-17 candidate region, were also sequenced. This analysis included the microtubule-associated protein tau that is the major component of the paired helical filaments observed in Alzheimer's disease. No pathogenic mutations were identified in either the tau gene or in any of the other genes analyzed.
Adult↗
A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43).
We report a novel mutation in the amyloid precursor protein gene (APP I716V) which probably leads to familial early onset Alzheimer's disease with an onset age in the mid 50s. Cells transfected with cDNAs bearing this mutation produce more A beta 1-42(43) than those transfected with wild-type APP and this effect is additive with that of the previously reported APP V717I mutation thus providing a novel approach for further increasing A beta 1-42(43) in model systems.
Age of Onset↗
Structure and alternative splicing of the presenilin-2 gene.
Missense mutations in the presenilin-1 (PS-1) and presenilin-2 (PS-2) genes have been shown to be causes of autosomal dominant Alzheimer's disease (the AD3 and AD4 loci, respectively). Alternative splicing has previously been reported in the PS-1 gene. In this study, elucidation of intron/exon boundary sequences revealed that PS-2 is encoded by 10 coding exons. In addition, PS-2 cDNA cloning and RT-PCR using RNA from a variety of normal tissues revealed the presence of alternatively spliced products. These products included species with in frame omissions of exon 8 and simultaneous omissions of exons 3 and 4.
Alternative Splicing↗
Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease.
The presenilin 1 gene has recently been identified as the locus on chromosome 14 which is responsible for a large proportion of early onset, autosomal dominantly inherited Alzheimer's disease (AD). We have elucidated the intron/exon structure of the gene and designed intronic primers to enable direct sequencing of the entire coding region (10 exons) of the presenilin gene in a large number of families. This strategy has enabled us to find a further two novel mutations in the gene. We discuss the distribution of mutations and the proportions of autosomal dominant AD with a mean age of onset below 60 years caused by mutations in this gene.
Alzheimer Disease↗