Lack of association between aspirin responsiveness and seven candidate gene haplotypes in patients with symptomatic vascular disease.

We studied the effect of prophylactic aspirin (ASA) ingestion on platelet function in 463 patients with stroke, transient ischemic attack (TIA) or acute coronary disease (ACD), using the Platelet Function Analyzer-100 (PFA-100). We correlated ASA responsiveness with haplotypes of seven candidate genes, selected for their documented role in platelet function, namely, the genes for integrins alpha2beta1and alphaIIbbeta3 (ITGA2, ITGA2B, and ITGB3), platelet glycoproteins Ibalpha and VI (GPIBA and GP6), the purinergic receptor P2Y1 (P2RY1), and prostaglandin H synthase 1 (PTGS1 = COX1). Non-responsiveness to ASA was defined as the failure of prior ASA ingestion to prolong the PFA-100 closure time (CT) when blood was perfused through cartridges coated with collagen plus epinephrine (CEPI-CT). ASA non-responsiveness was observed in 114 of 463 patients (24.6 %), but was not associated with haplotypes of any of the seven candidate genes. There was also no association between any haplotypes and the CT when blood was perfused through cartridges coated with collagen plus ADP (CADP-CT). The ASA non-responsive cohort had significantly increased whole blood platelet counts (p = 0.03) and plasma von Willebrand Factor antigen levels (p < 0.001), which likely contributes to resistance to the inhibitory effects of ASA in the PFA-100.

Lack of reproducibility of assessment of aspirin responsiveness by optical aggregometry and two platelet function tests.

The term aspirin-resistance describes the failure of aspirin to inhibit thromboxane A(2) production. Many new tests have become available for potentially measuring aspirin responses but some are non-specific and do not isolate COX-1 activity. We previously demonstrated that agreement between two tests (PFA-100 and VerifyNow-ASA) and light transmission aggregation (LTA) was no greater than would be expected by chance. In this study we re-tested the same patients using identical methods after 1 year to determine whether poor agreement might have been due to assessment in the acute phase and whether the results of the individual tests are consistent over time. Platelet function by all three tests was re-tested in the 72 patients who were alive and still receiving low dose ASA therapy one year after the first tests were performed. On re-testing the prevalence of ASA non-responsiveness compared with baseline was 10% vs 17% by the VerifyNow-ASA test, 25% vs 22% by the PFA-100(R), and 1% vs 5% by LTA. Agreement between the tests at 1 year remained poor (kappas: 0.02-0.17) and only one patient was identified as a non-responder by all three tests, in keeping with the theoretical differences between the tests. Within test comparisons of baseline vs 1 year showed moderate agreement for the PFA-100(R) (kappa = 0.44, 95% CI 0.19-0.68, p = 0.0006), a fair agreement for VerifyNow-ASA (kappa = 0.34, 0.04-0.64, p = 0.12) and poor agreement for LTA (kappa = 0.14, -0.11 -0.39, p = 0.24 for ADP; kappa = 0.09, -0.21-0.39, p = 0.41 for arachidonic acid). Agreement between the three tests in identifying aspirin non-responsiveness remained poor in patients who had been taking aspirin for at least 1 year follow-up. Reproducibility over time was no greater than chance for LTA and only moderate for VerifyNow-ASA and PFA-100(R). Lack of consistency over time in identification of apparently non-responsiveness individuals is likely to substantially undermine any ability of these tests to predict risk of recurrent vascular events.

A quantitative analysis of optic nerve axons in elderly control subjects and patients with Alzheimer's disease.

OBJECTIVE: To study the density and cross-sectional area of axons in the optic nerve in elderly control subjects and in cases of Alzheimer's disease (AD) using an image analysis system. METHODS: Sections of optic nerves from control and AD patients were stained with toluidine blue to reveal axon profiles. RESULTS: The density of axons was reduced in both the center and peripheral portions of the optic nerve in AD compared with control patients. Analysis of axons with different cross-sectional areas suggested a specific loss of the smaller sized axons in AD, i.e., those with areas less that 1.99 microm2. An analysis of axons >11 microm2 in cross-sectional area suggested no specific loss of the larger axons in this group of patients. CONCLUSIONS: The data suggest that image analysis provides an accurate and reproducible method of quantifying axons in the optic nerve. In addition, the data suggest that axons are lost throughout the optic nerve with a specific loss of the smaller-sized axons. Loss of the smaller axons may explain the deficits in color vision observed in a significant proportion of patients with AD.

Mitochondrial DNA haplogroups and risk of transient ischaemic attack and ischaemic stroke: a genetic association study.

BACKGROUND: Genetic factors have a role in the pathogenesis of ischaemic stroke, but the main genes involved have yet to be defined. Mitochondrial mechanisms have been implicated in the pathophysiology of acute stroke, but the role of mitochondrial DNA (mtDNA) has not been comprehensively studied. We investigated whether there is an association between mtDNA haplotypes and incidence of stroke. METHODS: The major European mtDNA haplogroups were identified in two independent subpopulations (n=950) from a study of occurrence of transient ischaemic attack (TIA) and ischaemic stroke and were compared with those of patients with acute coronary syndromes from the same populations (n=340) and with those of independent population controls (n=2939). FINDINGS: The presence of mtDNA sub-haplogroup K was significantly less frequent in patients with TIA or stroke than in controls in both subpopulations separately and in a pooled analysis (odds ratio 0.54, 95% CI 0.39-0.75, p<0.00001). This association remained highly significant after adjustment for multiple haplogroup comparisons. The association was significant for patients with TIA and stroke separately and was independent of known risk factors, but was not found for patients with acute coronary events. The mtDNA sub-haplogroup K was present in 8.7% of the total UK population controls and therefore confers a 4.0% (95% CI 2.2-5.7) reduction in population attributable risk of TIA and stroke. INTERPRETATION: Genetic variation of mtDNA sub-haplogroup K is an independent determinant of risk of cerebral, but not coronary, ischaemic vascular events. These findings implicate mitochondrial mechanisms in the aetiology of ischaemic stroke and provide a new means for the identification of individuals with a high susceptibility of developing ischaemic stroke.

Density and cross-sectional areas of axons in the olfactory tract in control subjects and Alzheimer's disease: an image analysis study.

OBJECTIVE: Using an image analysis system to determine whether there is loss of axons in the olfactory tract (OT) in Alzheimer's disease (AD). DESIGN: A retrospective neuropathological study. PATIENTS: Nine control patients and eight clinically and pathologically verified AD cases. MEASUREMENTS AND RESULTS: There was a reduction in axon density in AD compared with control subjects in the central and peripheral regions of the tract. Axonal loss was mainly of axons with smaller (<2.99 microm(2)) myelinated cross-sectional areas. CONCLUSIONS: The data suggest significant degeneration of axons within the OT involving the smaller sized axons. Loss of axons in the OT is likely to be secondary to pathological changes originating within the parahippocampal gyrus rather than to a pathogen spreading into the brain via the olfactory pathways.