Search PubMed⌕ Search

Biomedical subjects

A D Roses

Publications and source records attributed to A D Roses.

At least 37 records · Page 2Linked to original sources
PubMed2000

SNPing away at complex diseases: analysis of single-nucleotide polymorphisms around APOE in Alzheimer disease.

There has been great interest in the prospects of using single-nucleotide polymorphisms (SNPs) in the search for complex disease genes, and several initiatives devoted to the identification and mapping of SNPs throughout the human genome are currently underway. However, actual data investigating the use of SNPs for identification of complex disease genes are scarce. To begin to look at issues surrounding the use of SNPs in complex disease studies, we have initiated a collaborative SNP mapping study around APOE, the well-established susceptibility gene for late-onset Alzheimer disease (AD). Sixty SNPs in a 1.5-Mb region surrounding APOE were genotyped in samples of unrelated cases of AD, in controls, and in families with AD. Standard tests were conducted to look for association of SNP alleles with AD, in cases and controls. We also used family-based association analyses, including recently developed methods to look for haplotype association. Evidence of association (P</=.05) was identified for 7 of 13 SNPs, including the APOE-4 polymorphism, spanning 40 kb on either side of APOE. As expected, very strong evidence for association with AD was seen for the APOE-4 polymorphism, as well as for two other SNPs that lie <16 kb from APOE. Haplotype analysis using family data increased significance over that seen in single-locus tests for some of the markers, and, for these data, improved localization of the gene. Our results demonstrate that associations can be detected at SNPs near a complex disease gene. We found that a high density of markers will be necessary in order to have a good chance of including SNPs with detectable levels of allelic association with the disease mutation, and statistical analysis based on haplotypes can provide additional information with respect to tests of significance and fine localization of complex disease genes.

Age of Onset↗
PubMed2000

Pharmacogenetics and the practice of medicine.

"If it were not for the great variability among individuals medicine might as well be a science and not an art." The thoughts of Sir William Osler in 1892 reflect the view of medicine over the past 100 years. The role of physicians in making the necessary judgements about the medicines that they prescribe is often referred to as an art, reflecting the lack of objective data available to make decisions that are tailored to individual patients. Just over a hundred years later we are on the verge of being able to identify inherited differences between individuals which can predict each patient's response to a medicine. This ability will have far-reaching benefits in the discovery, development and delivery of medicines. Sir William Osler, if he were alive today, would be re-considering his view of medicine as an art not a science.

Delivery of Health Care↗
PubMed2000

Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease.

The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is associated with lowered parietal, temporal, and posterior cingulate cerebral glucose metabolism in patients with a clinical diagnosis of AD. To determine cognitive and metabolic decline patterns according to genetic risk, we investigated cerebral metabolic rates by using positron emission tomography in middle-aged and older nondemented persons with normal memory performance. A single copy of the APOE-4 allele was associated with lowered inferior parietal, lateral temporal, and posterior cingulate metabolism, which predicted cognitive decline after 2 years of longitudinal follow-up. For the 20 nondemented subjects followed longitudinally, memory performance scores did not decline significantly, but cortical metabolic rates did. In APOE-4 carriers, a 4% left posterior cingulate metabolic decline was observed, and inferior parietal and lateral temporal regions demonstrated the greatest magnitude (5%) of metabolic decline after 2 years. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a means for preclinical AD detection that will assist in response monitoring during experimental treatments.

Aged↗
PubMed2000

Analysis of association at single nucleotide polymorphisms in the APOE region.

The discussion of the prospects of using a dense map of single nucleotide polymorphisms (SNPs) to identify disease genes with association analysis has been extensive. However, there is little empiric evidence to support this strategy. To begin to examine the practical issues surrounding this methodology, we identified 10 SNPs in the region immediately surrounding the apolipoprotein E locus (APOE), an established susceptibility gene for Alzheimer disease. Our goal was to examine patterns of allelic association to begin to investigate the question of whether APOE could have been identified using SNPs. Our strongest evidence of association was at the 2 SNPs immediately flanking APOE.

Age of Onset↗
PubMed2000

Reversal of presynaptic deficits of apolipoprotein E-deficient mice in human apolipoprotein E transgenic mice.

Apolipoprotein E genotype is an important risk factor of Alzheimer's disease, which is associated with the degeneration of distinct brain neuronal systems. In the present study we employed apolipoprotein E-deficient mice and human apolipoprotein E3 and apolipoprotein E4 transgenic mice on a null mouse apolipoprotein E background, to examine the extent to which distinct brain neuronal systems are affected by apolipoprotein E and the isoform specificity of this effect. This was pursued by histological and autoradiographic measurements utilizing neuron specific presynaptic markers. The results thus obtained revealed significant reductions in the levels of brain cholinergic and noradrenergic nerve terminals in young apolipoprotein E-deficient mice and no changes in brain dopaminergic nerve terminals. These cholinergic and noradrenergic presynaptic derangements were ameliorated similarly in human apolipoprotein E3 and apolipoprotein E4 transgenic mice. In the case of the cholinergic system, this resulted in complete reversal of the presynaptic deficits, whereas in the case of the noradrenergic neurons the amelioration was partial. These findings suggest that brain cholinergic and noradrenergic neurons are markedly more dependent on brain apolipoprotein E than brain dopaminergic neurons and that the isoform specificity of these effects is not apparent at a young age under non-challenged conditions.

Acetylcholine↗
PubMed2000

Susceptibility of transgenic mice expressing human apolipoprotein E to closed head injury: the allele E3 is neuroprotective whereas E4 increases fatalities.

Apolipoprotein E, the major brain lipid-binding protein, is expressed in humans as three common isoforms (E2, E3 and E4). Previous studies revealed that the allele apolipoprotein E4 is a major genetic risk factor of Alzheimer's disease and that traumatic brain injury is associated with increased risk for developing this disease. Furthermore, it has been suggested that the effects of traumatic head injury and apolipoprotein E4 in Alzheimer's disease are synergistic. To test the hypothesis that the apolipoprotein E genotype affects susceptibility to brain injury, we subjected transgenic mice, expressing either human apolipoprotein E3 or human apolipoprotein E4 on a null mouse apolipoprotein E background and apolipoprotein E-deficient knockouts, to closed head injury and compared mortality, neurological recovery and the extent of brain damage of the survivors. More than 50% of the transgenic mice expressing human apolipoprotein E4 died following closed head injury, whereas only half as many of the transgenic mice expressing human apolipoprotein E3, and of the control and apolipoprotein E-deficient mice died during this period (P<0.02). A neurological severity score used for clinical assessment of the surviving mice up to 11 days after closed head injury revealed that the four mouse groups displayed similar severity of damage at 1h following injury. At three and 11 days post-injury, however, the neurological severity scores of the transgenic mice expressing human apolipoprotein E3 were significantly lower than those of the other three groups whose scores were similar, indicating better recovery of the transgenic mice expressing human apolipoprotein E3. Histopathological examination of the mice performed 11 days post-injury revealed, consistent with the above neurological results, that the size of the damaged brain area of the transgenic mice expressing human apolipoprotein E3 was smaller than that of the other head-injured groups. These findings show that transgenic mice expressing human apolipoprotein E4 are more susceptible than those expressing apolipoprotein E3 to closed head injury. We suggest that this effect is due to both a protective effect of apolipoprotein E3 and an apolipoprotein E4-related pathological function.

Alleles↗
PubMed2000

Identification of novel genes in late-onset Alzheimer's disease.

Four genes affecting Alzheimer's Disease (AD)(AP, PS1, PS2, and APOE) have been identified and a fifth potential gene localized to chromosome 12. Collectively, these genes explain at most half of the genetic effect in AD. Understanding the genetics of AD is critical to developing new treatments. The quest to find the remaining AD genes led us to undertake a large genomic screen using over 466 families (730 affected sibpairs) in late-onset AD. In conjunction with this increase in power, we initiated several novel approaches to identify potential AD-related genes. This included stratification of the data into an autopsy-confirmed subset of 199 AD families. Each of these targeted analyses resulted in the identification of novel regions containing potential AD genetic risk factors. Our most significant finding was on chromosome 9 in the autopsy-confirmed subset where we obtained an MLS of 4.31. These approaches, together with new methodologies such as conditional linkage analysis, generalized family-based association tests (PDT), and a new generation of genetic markers (SNPs), opens the door for additional AD gene discovery. Such strategies are necessary if we are to understand the subtle and complex threads that, woven together, create the intricate tapestry of AD.

Age of Onset↗
PubMed2000

Fine mapping of the chromosome 12 late-onset Alzheimer disease locus: potential genetic and phenotypic heterogeneity.

Apolipoprotein E (APOE) is the only confirmed susceptibility gene for late-onset Alzheimer disease (AD). In a recent genomic screen of 54 families with late-onset AD, we detected significant evidence for a second late-onset AD locus located on chromosome 12 between D12S373 and D12S390. Linkage to this region was strongest in 27 large families with at least one affected individual without an APOE-4 allele, suggesting that APOE and the chromosome 12 locus might have independent effects. We have since genotyped several additional markers across the region, to refine the linkage results. In analyzing these additional data, we have addressed the issue of heterogeneity in the data set by weighting results by clinical and neuropathologic features, sibship size, and APOE genotype. When considering all possible affected sib pairs (ASPs) per nuclear family, we obtained a peak maximum LOD score between D12S1057 and D12S1042. The magnitude and location of the maximum LOD score changed when different weighting schemes were used to control for the number of ASPs contributed by each nuclear family. Using the affected-relative-pair method implemented in GENEHUNTER-PLUS, we obtained a maximum LOD score between D12S398 and D12S1632, 25 cM from the original maximum LOD score. These results indicate that family size influences the location estimate for the chromosome 12 AD gene. The results of conditional linkage analysis by use of GENEHUNTER-PLUS indicated that evidence for linkage to chromosome 12 was stronger in families with affected individuals lacking an APOE-4 allele; much of this evidence came from families with affected individuals with neuropathologic diagnosis of dementia with Lewy bodies (DLB). Taken together, these results indicate that the chromosome 12 locus acts independently of APOE to increase the risk of late-onset familial AD and that it may be associated with the DLB variant of AD.

Age of Onset↗
PubMed2000

Cognitive function and apolipoprotein E in very old adults: findings from the Nun Study.

OBJECTIVES: The epsilon4 allele of apolipoprotein E (APOE) has been associated with Alzheimer' s disease and with milder forms of cognitive impairment. We investigated the possibility that the absence of the epsilon4 allele may predict the maintenance of high cognitive function among very old individuals. METHODS: Our data are from the Nun Study, a longitudinal study of aging and Alzheimer's disease in 678 Catholic sisters. All sisters participate in annual functional exams that include the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery of cognitive tests. High cognitive function was defined as intact scores on five of the CERAD tests. A total of 241 participants aged 75 to 98 met this criterion at the first exam. RESULTS: Findings showed that 62% of the 241 participants maintained intact scores on the five CERAD tests throughout their participation in the study. Life table analyses indicated that those without the APOE epsilon4 allele spent more time with intact cognitive function than those with the epsilon4 allele (p = .007). Cox regression analyses indicated that those without the epsilon4 allele had half the risk of losing their intact status during the study when compared with those with the epsilon4 allele (p < .01). DISCUSSION: Our findings suggest that the APOE epsilon4 allele may be included among the variables that predict high cognitive function in cognitively intact, very old adults. Although the presence or absence of the epsilon4 allele is known to be related to the risk of dementia, it also appears to be related to maintaining high levels of cognitive function in old age.

Aged↗
PubMed2000

Intraventricular infusion of apolipoprotein E ameliorates acute neuronal damage after global cerebral ischemia in mice.

The ability of intraventricular infusion of apolipoprotein E (apoE) to reduce neuronal damage after global cerebral ischemia was investigated in apoE-deficient and wild-type mice. ApoE (5 microg/mL lipid-conjugated derived from human plasma; 1 microL/h, continuous infusion) significantly reduced neuronal damage in the caudate nucleus and CA2 pyramidal cell layer by approximately 50% in apoE-deficient mice after global ischemia compared to vehicle infusion. In wild-type mice infused with apoE, there was a trend for ischemic neuronal damage to be reduced. ApoE-infused mice had a marked reduction in 4-hydroxynonenal immunoreactivity, as a marker of lipid peroxidation. The results show that the presence of apoE at or after the time of injury can be neuroprotective, possibly via an anti-oxidant mechanism.

Aldehydes↗
PubMed2000

Idiosyncratic reactions to drugs: can medicine response profiles provide a dynamic drug surveillance system?

Over the next few years it will be possible to use advances in single nucleotide polymorphism map technology to correlate information from patients' DNA with their response to medicines. This provides significant opportunities to enhance current drug surveillance systems by collecting data that would enable rare serious adverse events to be predicted in subsequent patients before the medicine is prescribed. Reasonable discussion regarding perceived or real barriers to this surveillance concept is required to realize the significant patient benefits which will accrue from this system.

Drug-Related Side Effects and Adverse Reactions↗
PubMed2000

Increased neuronal damage and apoE immunoreactivity in human apolipoprotein E, E4 isoform-specific, transgenic mice after global cerebral ischaemia.

Apolipoprotein E (apoE, protein; APOE, gene) is expressed as three isoforms in humans (E2, E3, E4). The APOE-epsilon4 allele is associated with a poor outcome in patients after head injury of which ischaemic brain damage is a contributor of mortality and morbidity. The aim of the study was to determine whether mice expressing human APOE-epsilon4 displayed more extensive ischaemic neuronal damage 72 h after transient global ischaemia compared with mice which express human APOE-epsilon3. APOE-epsilon3 and -epsilon4 transgenic mice, under the control of a human promoter, were used which express human APOE in neurons and glia. Ischaemic neuronal damage in the CA1 pyramidal cell layer in the APOE-epsilon4 transgenic mice was significantly greater than in the APOE-epsilon3 mice after global ischaemia (36.4+/-8.9%, 18.2+/-7.3%; P<0.05). This was associated with more extensive neuronal apoE immunoreactivity in the CA1 pyramidal cell layer in the APOE-epsilon4 transgenic mice compared with APOE-epsilon3 transgenic mice. In contrast, in the caudate nucleus, there were similar levels of ischaemic neuronal damage in the APOE-epsilon3 and -epsilon4 transgenic mice (39.2 +/-10.1%; 44.6+/-8.4%, P = 0.32). In the caudate, similar numbers of neurons were immunostained for apoE in the APOE-epsilon3 and -epsilon4 transgenic mice. The present study demonstrated that the APOE-epsilon4 allele is associated with an increased vulnerability of a specific brain region to the effects of global ischaemia, which is closely associated with an increase in neuronal apoE. The data extend previous work and are consistent with an association of the APOE-epsilon4 allele with a poor outcome after acute brain injury in humans.

Alleles↗
PubMed1999

Analysis of association between Alzheimer disease and the K variant of butyrylcholinesterase (BCHE-K).

Butyrylcholinesterase (BCHE) is an enzyme expressed in most human tissues. Recently, an increased odds of carrying the K variant of BCHE (BCHE-K) was reported among Alzheimer disease (AD) cases as compared with controls. We tested our data set of 245 sporadic AD cases and 241 controls for an association between BCHE-K, APOE4, and AD using logistic regression and chi-square analyses. The sib transmission disequilibrium test (S-TDT) was also used to test for differences in BCHE-K allele frequencies between 163 discordant sib-pairs selected from multiplex AD families. No statistically significant differences were noted between BCHE-K case and control allele frequencies even after stratifying by APOE4 status. S-TDT analysis between the BCHE-K variant and AD was also not significant (P = 0.52). We conclude that BCHE-K is not a major genetic risk factor for AD in our study population.

Adult↗
PubMed1999

Increased neuronal damage in apolipoprotein E-deficient mice following global ischaemia.

There is accumulating evidence that apolipoprotein E (apoE) plays a role in regulating the response to and outcome following brain injury. The present study compared the histological outcome and recovery following an episode of global ischaemia in apoE-deficient mice and wild-type littermates (12-week-old males, n = 8 per group). Transient global ischaemia was induced for a period of 17 min and the animals were allowed to recover for 72 h. Transient global ischaemia induced selective neuronal degeneration in several brain regions in wild-type mice. There was statistically significant increased ischaemic neuronal damage in apoE-deficient mice compared with wild-type mice in six of the seven regions examined (hippocampal regions CA1, CA3/CA4 and dentate gyrus; thalamus; cortex and caudate nucleus; P < 0.05). The data substantiate a role for apoE in modifying the response of the CNS to acute injury.

Alleles↗