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Biomedical subjects

R Clarnette

Publications and source records attributed to R Clarnette.

10 recordsLinked to original sources
PubMed2006

Quantitative MR imaging R2 relaxometry in elderly participants reporting memory loss.

BACKGROUND AND PURPOSE: In Alzheimer disease (AD), elevated brain iron concentrations in gray matter suggest a disruption in iron homeostasis, while demyelination processes in white matter increase the water content. Our aim was to assess whether the transverse proton relaxation rate, or R2, an MR imaging parameter affected by changes in brain iron concentration and water content, was different in elderly participants with mild to severe levels of cognitive impairment compared with healthy controls. METHODS: Twelve elderly participants reporting memory problems and 11 healthy volunteers underwent single-spin-echo MR imaging in a 1.5T scanner, with subsequent neuropsychological testing. R2 data were collected from 14 brain regions in cortical and subcortical gray and white matter. Those with memory complaints were separated into 2 further subgroups: MC1 (no objective cognitive impairment) and MC2 (mild to severe objective cognitive impairment). RESULTS: Mean brain R2 values from the 11 controls correlated strongly (r = 0.94, P < .0001) with reference brain iron concentrations for healthy adults. R2 values in the MC1 and MC2 subgroups were significantly higher in the right temporal cortex and significantly lower in the left internal capsule, compared with healthy controls. R2 values in the MC2 subgroup were significantly lower in the left temporal and frontal white matter, compared with healthy controls. CONCLUSIONS: R2 differences between both subgroups and the healthy controls suggest iron has increased in the temporal cortex, and myelin has been lost from several white matter regions in those with memory complaints, consistent with incipient AD pathogenesis and biochemical data.

Aged↗
PubMed2004

Oestrogen replacement therapy may improve memory functioning in the absence of APOE epsilon4.

There is currently intense controversy regarding the use of hormone replacement therapy (HRT) in postmenopausal women, in relation to its therapeutic efficacy in Alzheimer's disease (AD). It has been suggested that the benefits of HRT may be modified by apolipoprotein E (APOE) genotype (the major genetic risk factor for AD). Here we report the findings of the first study designed to systematically explore the interaction of (a) oestrogen replacement therapy (ERT) and (b) possession of an epsilon4 allele of APOE on specific elements of episodic learning and memory that are commonly used indices of age-related cognitive decline. This data represents a cross-sectional analysis of the interaction of ERT and APOE genotype on learning and memory in a cohort of 181 healthy postmenopausal women [ERT users (n = 101, mean age 65.40 +/- 6.34); ERT non-users (n = 80, mean age 67.03 +/- 6.80)] residing in Perth, Western Australia. The highest level of learning (trials 2-5; P < 0.05) and memory (e.g. total number of items recalled; P < 0.05) performance was observed in women taking ERT who were not carriers of the APOE epsilon4 allele. APOEepsilon4 carriers receiving ERT performed no better on episodic memory testing than APOE epsilon4 carriers who were not receiving ERT. These cognitive differences related to genetic profile, were noted on both recall and recognition (P = 0.005) tests of memory. The findings have significance for evaluating whether and when ERT may be clinically indicated. Specifically, ERT may benefit the cognitive functioning of women not carrying the APOE epsilon4 allele.

Aged↗
PubMed2001

An investigation of 2 techniques for optimizing joint surface congruency using multiple cylindrical osteochondral autografts.

PURPOSE: To compare 2 techniques for optimizing joint congruency for miniature osteochondral autografting in the knee: intrinsic postoperative forces acting on overdrilled autografts protruding from the femur versus alignment by a surgeon at the time of grafting. TYPE OF STUDY: Controlled animal model experiment. METHODS: A full-thickness cartilage defect was created on the weight-bearing surface of the medial femoral condyle of 13 mature sheep. Three 4.5 x 10 mm cylindrical autografts were inserted into 14-mm deep recipient holes such that the grafts were held in place by side-wall friction alone. One treatment group received grafts that were delivered flush with the surrounding cartilage and the second group received grafts that were left 2-mm proud of the joint surface. RESULTS: Three months postoperatively, the proud grafts had been repositioned by weight bearing but perigraft fissuring and fibroplasia, and subchondral cavitations were serious complications. It is suspected that these complications were caused by excessive motion between the graft and recipient site in the proud grafts. CONCLUSIONS: Grafts should be delivered flush with the joint surface when performing osteochondral transfers to avoid graft micromotion and the consequent interference with graft integration and function.

Animals↗
PubMed1999

The -491AA polymorphism in the APOE gene is associated with increased plasma apoE levels in Alzheimer's disease.

Recent evidence suggests that a polymorphism in the regulatory region of the apolipoprotein E gene (APOE) is associated with an increased risk for developing Alzheimer's disease (AD) independent of that conveyed by the epsilon4 allele of APOE. Previous work by our group indicated that plasma apolipoprotein E (apoE) levels were elevated in AD, raising the possibility that the -491 genotype might modify AD risk by increasing expression of the APOE gene. In a total of 638 individuals the -491AA genotype was significantly associated with AD (P < 0.005) while the TT genotype was associated with controls (P < 0.005). In 138 individuals the AA genotype showed significantly higher plasma apoE levels, independent of epsilon4 and AD status (P < 0.01) as well as within control and AD groups (P < 0.05). Within the AD group the AA genotype showed increased apoE levels when compared to AA controls (P < 0.0001). These results suggest that the -491 AA genotype is associated with increased plasma apoE levels, providing a potential basis for elucidating how that genotype increases the risk for developing AD.

Alzheimer Disease↗
PubMed1998

No association of presenilin-1 intronic polymorphism and Alzheimer's disease in Australia.

We screened 703 Australian subjects for an intronic polymorphism in the presenilin-1 (PS-1) gene. PS-1 intronic allele 1 homozygosity was not associated with individuals with early- or late-onset sporadic Alzheimer's disease (EOAD or LOAD). Carriers for the PS-1 intronic allele 1 were also not associated with significantly increased risk for AD regardless of gender. Our results for the Australian population are consistent with those of recent reports for other populations and do not support the conclusion that the PS-1 intronic polymorphism is associated with AD.

Adult↗
PubMed1997

Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype.

Eleven early-onset dementia families, all with affected individuals who have either presented clinical symptoms of early onset familial Alzheimer's disease (EOFAD) or have been confirmed to have EOFAD by autopsy, and two early onset cases with biopsy-confirmed AD pathology, were screened for missense mutations in the entire coding region of presenilin-1 (PS-1) and -2 (PS-2) genes. Missense mutations were detected by direct sequence analysis of PCR products amplified from genomic DNA templates of affected individuals. Three pedigrees were attributable to known mutations in the PS-1 gene: P264L, E280A and the splice acceptor site (G to T) mutation, which results in the deletion of residues 290-319 of PS-1 (PS-1 delta 290-319). In a fourth pedigree, a novel PS-1 mutation was identified in exon 7 (M233T), which is homologous to a pathogenic PS-2 mutation (M239V), and is characterized by a very early average age of onset (before the age of 35). In one early onset case, another novel PS-1 mutation was identified in exon 8 (R278T). Of the five remaining families and the other early onset case, none have missense mutations in the PS-1 or PS-2 genes, or in exon 16 and 17 of the APP gene. Moreover, two of the PS-1 mutations, PS-1 delta 290-319 and R278T, are associated with the co-presentation of familial spastic paraparesis (FSP) in some of the affected family members. Our data raise the possibility that the phenotypic spectrum associated with PS-1 mutations may extend beyond typical FAD to include FSP, a disease heretofore unsuspected to bear any relationship to FAD. In addition, our data suggest that other novel EOFAD loci, in addition to APP and the presenilin genes, are involved in the aetiology of up to 50% of EOFAD cases.

Adult↗
PubMed1997

Increased plasma apolipoprotein E (apoE) levels in Alzheimer's disease.

We measured the concentration of apolipoprotein E (apoE) in plasma from 184 non-fasted subjects in order to determine whether important variations might exist linking plasma apoE levels to clinical phenotypes among early and late onset sporadic Alzheimer's disease (AD) and Down's syndrome (DS). A significant increase in the level of plasma apoE was observed in non-fasted late-onset AD patients (with a mean level of 3.26 +/- 0.08 microgram apoE/mg total protein for n = 84 patients) when compared with the plasma apoE levels of control individuals (mean of 2.32 +/- 0.10 microgram apoE/mg total protein, n = 51 patients; P < 0.001). A similar increase was found for non-fasted early-onset AD patients (mean of 3.69 +/- 0.17 microgram apoE/mg total protein, n = 20) when compared with the plasma apoE levels of control individuals (P < 0.001). Plasma apoE levels for DS patients did not differ significantly from those of controls (P > 0.05). The association of elevated plasma apoE levels in AD may be relevant to clarifying the mechanism(s) whereby apoE isoforms specify differential risk for development of AD.

Adult↗
PubMed1995

ApoE genotypes in Australia: roles in early and late onset Alzheimer's disease and Down's syndrome.

We studied the apoE genotypes of 279 Australians in order to determine what relationships might exist in this group between apoE genotype and dementia associated with either early- or late-onset sporadic Alzheimer's disease (AD) or with Down's syndrome (DS). ApoE epsilon 4 allele frequency was increased in Australians with either early-onset sporadic AD (p < 0.002) or late-onset sporadic AD (p < 0.0001) and apoE epsilon 2 allele frequency was decreased in the late-onset sporadic AD group (p < 0.01). The apoE genotype distribution among patients with DS was not different from that of the control group. One individual with DS and an apoE epsilon 4/epsilon 4 genotype developed dementia at the earliest age of dementing DS patients, consistent with a role for apoE epsilon 4 in determining age of onset of dementia in AD and DS. Another DS patient with an apoE epsilon 2/epsilon 3 genotype developed dementia within an age range similar to that of four demented DS patients with an apoE epsilon 3/epsilon 3 genotype, an observation which would appear inconsistent with the proposed protective effect of apoE epsilon 2 to delay onset of dementia in DS. These results extend the evidence that the apoE genotype, particularly apoE epsilon 4, modulates dementia in early- and late-onset sporadic AD and DS. The protective role of apoE epsilon 2 in DS, however, may vary among different populations or ethnic groups.

Age of Onset↗