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R Crook

Publications and source records attributed to R Crook.

At least 19 recordsLinked to original sources
PubMed2000

Variant Alzheimer's disease with spastic paraparesis: clinical characterization.

OBJECTIVE: To present the clinical, neuroimaging, and electrophysiologic characteristics of a variant AD phenotype. BACKGROUND: The authors have identified a large Finnish kindred with presenile dementia and spastic paraparesis due to deletion of exon 9 of presenilin 1. Neuropathologic analysis showed unusual cortical "cotton wool" plaques, immunoreactive for the beta-amyloid peptide but lacking congophilic cores. PATIENTS AND METHODS: Twenty-two affected individuals (16 men and 6 women) were identified in four successive generations. All surviving five patients were examined and subjected to molecular genetic analysis. In addition, the neurologic records of nine deceased patients were evaluated. Electrophysiologic investigations were available in eight cases. CT or MRI of the head had been performed on 11 patients and PET was performed on three patients. RESULT: The mean age at onset (+/-SD) was 50.9 +/- 5.2 years (range 40 to 61 years). Memory impairment was present in all patients. Memory impairment appeared simultaneously with or was preceded by walking difficulty due to spasticity of the lower extremities (10/14). Impaired fine coordination of hands (9/14) and dysarthria (6/14) in some patients suggested cerebellar involvement. EEG showed intermittent generalized delta-theta activity. Head MRI showed temporal and hippocampal atrophy; PET showed bilateral temporo-parietal hypometabolism. CONCLUSION: Spastic paraparesis or brisk stretch reflexes of lower extremities or clumsiness of hands combined with dementia suggests this variant of AD.

Age of Onset↗
PubMed1999

Neurodegenerative diseases of Guam: analysis of TAU.

Mutations in the tau gene have been described in families affected by frontotemporal dementia with parkinsonism linked to chromosome 17. The authors performed a genetic and biochemical analysis of this gene and its product in the parkinsonism dementia complex of Guam, a disorder characterized by the extensive formation of neurofibrillary tangles. The tau gene is not a primary cause of the parkinsonism dementia complex of Guam.

Aged↗
PubMed1999

Genetic variability at the amyloid-beta precursor protein locus may contribute to the risk of late-onset Alzheimer's disease.

In a series of sibpairs with late onset Alzheimer's disease, we have examined the segregation of the loci involved in the early onset, autosomal dominant form of the disorder by using flanking microsatellite repeat markers: thus we have used APP-PCR3 and D21S210 to examine the segregation of the amyloid-beta precursor protein (APP) gene, the markers DI 4S77 and D14S284 to examine the segregation of the presenilin 1 (PSI) gene and the markers D1S227, D1S249 and D1S419 to examine the segregation of presenilin 2 (PS2). We carried out our analyses on the whole dataset of 291 affected sibpairs, and on subsets comprising those sibpairs in which neither had an apolipoprotein E4 allele (65 affected sibpairs) and those in which both had an apolipoprotein E4 allele (165 affected sibpairs). We used the programs SPLINK to generate allele frequencies and MAPMAKER/SIBS to analyze our results. We examined the segregation of the markers D19S908 and D19S918 that are close to the apolipoprotein E (ApoE) gene as a positive control to assess whether the methods we are employing have the capability to identify known loci. The sibpair approach to the identification of genetic risk loci is relatively insensitive as indicated by the failure of the ApoE locus to reach statistical significance (P = 0.06). Nevertheless, these data suggest that neither the PS1 nor the PS2 gene is a major locus for late-onset AD, but that the APP gene cannot be ruled out as a risk locus in those sibships without an E4 allele (P = 0.014). The possibility that APP is indeed a locus for late onset disease will need confirmation in other series of familial cases.

Age of Onset↗
PubMed1999

No pathogenic mutations in the beta-synuclein gene in Parkinson's disease.

We present 11 families consistent with autosomal dominant inheritance of probable Parkinson's disease (PD). Although excluded as a cause of disease in these kindreds, mutations in the alpha-synuclein gene have been implicated in familial PD. The beta-synuclein gene is highly homologous, expressed in the nervous system and thus is a good candidate gene for PD. Multipoint linkage analysis was either equivocal or excluded 5q35 haplotype sharing among affected family members. Sequencing the translated exons of the beta-synuclein gene failed to identify any pathogenic mutation.

Adult↗
PubMed1999

A novel candidate presenilin-1 interacting protein containing tetratricopeptide repeats.

The yeast two-hybrid system, immunofluorescence and co-immunoprecipitation techniques were used to identify a novel candidate protein with which presenilin-1 (PS-1) interacts. This interacting protein, the gene of which is encoded on chromosome 16, contains two tetratricopeptide repeats (TPR) that are known to mediate interactions between proteins, appears to be primarily localized to the cytoplasm of transfected HEK293 cells, and is expressed in brain. Preliminary yeast two-hybrid data suggests this candidate may interact with both heat shock protein-90 and heat shock protein-70 and thus may be a novel member of TPR-containing proteins which interact with this complex.

Alzheimer Disease↗
PubMed1999

No association between the alpha-2 macroglobulin I1000V polymorphism and Alzheimer's disease.

Recent reports have suggested that variability in the alpha2-macroglobulin gene is a genetic risk factor for Alzheimer's disease. Here we have both tested a common polymorphism in the gene (I1000V) for association with the disease in a four-site case control study design, and tested the locus for linkage in a large series of sibpairs afflicted with late onset disease. Our results fail to show an association between this polymorphism and disease.

Age of Onset↗
PubMed1999

Association between coding variability in the LRP gene and the risk of late-onset Alzheimer's disease.

We have sequenced the entire (89 exons) open reading frame of the LRP gene in 12 cases of Alzheimer's disease (AD) from Northern France. We have found no novel changes but confirm the occurrence of a polymorphism in exon 6 of the gene (A216V). This polymorphism is rare (2.8% of controls) and is in linkage equilibrium with previously reported polymorphisms. The V216 allele is negatively associated with the disease in a large case-controlled series. These data suggest that the LRP receptor may be involved in the pathobiology of AD, but the association that we report here cannot explain the previously reported genetic data implicating the LRP gene in AD. If the LRP gene is a major site of genetic variability leading to AD, there must be other biologically relevant variability in promoter or other regulatory elements of this large gene.

Aged↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1999

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↗
PubMed1998

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↗
PubMed1998

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↗
PubMed1998

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↗
PubMed1998

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↗
PubMed1998

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↗