Estrogen therapy and risk of cognitive decline: results from the Women's Estrogen for Stroke Trial (WEST)

OBJECTIVE: This study was undertaken to assess whether estrogen therapy (ET) reduces the risk of cognitive decline in women with cerebrovascular disease. STUDY DESIGN: We conducted a randomized, double-blind trial of estradiol 17beta versus placebo for secondary stroke prevention in 664 postmenopausal women with a recent stroke or transient ischemic attack. The Mini-Mental State Examination (MMSE) and 5 domain measures were obtained at baseline and exit. RESULTS: Among 461 women withdrawn alive without stroke, ET did not have a significant effect on cognitive measures after an average of 3 years (relative risk of MMSE decline: 0.74, 95% CI, 0.49-1.13). In women with normal MMSE at entry, estrogen was associated with less decline (relative risk, 0.46, 95% CI, 0.24-0.87). CONCLUSION: In this study, estradiol did not have significant effects on cognitive measures. However, in women with normal function at baseline, there may be a benefit for ET in reducing the risk for cognitive decline.     

Association between impaired insulin sensitivity and stroke

BACKGROUND: Prior research has indicated an association between insulin resistance and stroke; we sought to determine if this association persists after adjusting for stroke risk factors, including glycemic control. METHODS: We used data from the Third National Health and Nutrition Survey (1988-1994), including participants aged > or =40 years. We assessed insulin sensitivity using the homeostasis model assessment (HOMA): HOMA = (FPGSI x FPI)/22.5, where FPGSI refers to fasting plasma glucose (mmol/l) and FPI refers to fasting plasma insulin (microU/l). Increasing HOMA indicates decreasing insulin sensitivity. We used glycosylated hemoglobin (HbA1c) to measure glycemic control. Multivariable logistic regression analysis was used to identify factors that were independently associated with stroke. RESULTS: Among 3,844 participants, 168 (4%) reported a stroke history. Participants with stroke had lower insulin sensitivity than participants without stroke: HOMA mean +/- standard deviation, 4.0 +/- 4.0 vs. 3.3 +/- 3.0; p = 0.022. HOMA was independently associated with stroke (odds ratio 1.06, 95% CI: 1.01-1.12; adjusted for age, hypertension, myocardial infarction, claudication, activity, and HbA1c). The strength of the association between HOMA and stroke was similar to the association between claudication and stroke (index R(2): 0.0032 vs. 0.0036). CONCLUSIONS: Impaired insulin sensitivity is independently associated with stroke, even after adjustment for glycemic control.     

The inhibition of imitative and overlearned responses: a functional double dissociation

Neuropsychological research has established that the inhibition of dominant response tendencies is a function of the prefrontal cortex. These inhibitory mechanisms are tested using tasks like the Stroop task, in which the prepotency of the dominant response is based on a learned relationship of stimulus and response. However, it has also been reported that patients with prefrontal lesions may have problems inhibiting imitative responses. The question arises of whether the inhibition of overlearned and imitative responses entails the same or different functional mechanisms and cortical networks. In a recent neuropsychological study with prefrontal patients we found first evidence for such a dissociation. The present fMRI study further investigated this question by directly comparing brain activity in the inhibition of overlearned and imitative response tendencies. It emerges that response inhibition in the two tasks involves different neural networks. While the inhibition of overlearned responses requires a fronto-parietal network involved in interference control and task management, the inhibition of imitative responses involves cortical areas that are required to distinguish between self-generated and externally triggered motor representations. The only frontal brain area that showed an overlap was located in the right inferior frontal gyrus and is probably related to the generation of the stop signal.     

Advance preparation and stimulus-induced interference in cued task switching: further insights from BOLD fMRI

To switch from one cognitive task to another is thought to rely on additional control effort being indicated by performance costs relative to repeating the same task. This switch cost can be reduced by advance task preparation. In the present experiment the nature of advance preparation was investigated by comparing a situation where an explicit task cue was presented 2000 ms in advance of the target stimulus (CTI-2000) with a situation where cue and target were presented in close succession (CTI-100). We mapped the blood-oxygenation-level-dependent (BOLD) activation correlates of switch-related control effort and advance task preparation to test alternative explanations why advance preparation is reducing switch costs. A previously reported control-related cortical network of frontal and parietal brain areas emerged that was more strongly activated for switching between tasks. However, this was true exclusively for CTI-100 where no advance task preparation was possible. At CTI-2000 these same brain areas were equally engaged in both switch and repeat trials. For some of these areas, this common activation was time-locked to the presentation of both the cue as well as the target. Other areas were exclusively associated with target processing. The overall pattern of results suggests that advance task preparation is a common process of pre-activating (cue-locked activation) the currently relevant task set which does not face interference from a persisting N - 1 task set. During target processing the same brain areas are re-engaged (subsequent target-locked activation) to apply the pre-activated task set. Though being common to repeat and switch trials, advance preparation has a differential benefit for switch trials. This is because the instructed task set has time to settle into a stable state, thus becoming resistant against disruption from the previous task set, which is retrieved by the current target stimulus.     

Management of atherothrombosis with clopidogrel in high-risk patients with recent transient ischaemic attack or ischaemic stroke (MATCH): study design and baseline data

BACKGROUND: The CAPRIE study showed the superiority of clopidogrel over acetylsalicylic acid (ASA) for reducing the combined risk of major atherothrombotic events in patients with recent myocardial infarction (MI), recent ischaemic stroke (IS) or established peripheral arterial disease. The benefit of clopidogrel over ASA is amplified in high-risk patients. Proof of concept for the benefit of clopidogrel in addition to ASA in patients with coronary manifestations of atherothrombosis was provided by the CURE trial. METHODS: MATCH is a randomized, double-blind, placebo-controlled trial that compares clopidogrel and ASA versus clopidogrel alone in high-risk patients with recently symptomatic cerebrovascular disease. Eligible patients have experienced a transient ischaemic attack (TIA) or IS within the last 3 months and have evidence of at least 1 additional risk factor within the last 3 years (prior IS, MI, stable or unstable angina pectoris, diabetes or symptomatic peripheral arterial disease). Patients were randomized to receive ASA 75 mg once daily or placebo, with both groups receiving clopidogrel 75 mg once daily as part of standard therapy. The primary end point is the composite of IS, MI, vascular death and rehospitalization for an acute ischaemic event. The duration of treatment and follow-up is 18 months for each patient. RESULTS: Enrollment was completed in April 2002, with 7,599 patients randomized to receive the study medication. The mean age at randomization was 66 years, and the qualifying event was IS in 78.9% of patients and TIA in 21.1%. The baseline features of the study cohort indicate a population that is at a high risk for atherothrombotic recurrence. CONCLUSION: MATCH is a major ongoing trial that will provide important data on the benefit of clopidogrel and ASA compared with clopidogrel alone for reduction of vascular ischaemic events in patients with recent TIA or IS who are at high risk of atherothrombotic event recurrence.     

Prevention of a first stroke: a review of guidelines and a multidisciplinary consensus statement from the National Stroke Association

Objective  To establish, in a single resource, up-to-date recommendations for primary care physicians regarding prevention strategies for a first stroke. Participants  Members of the National Stroke Association's (NSA's) Stroke Prevention Advisory Board and Cedars-Sinai Health System Department of Health Services Research convened on April 9, 1998, in an open meeting. The conference attendees, selected to participate by the NSA, were recognized experts in neurology (9), cardiology (2), family practice (1), nursing (1), physician assistant practices (1), and health services research (2). Evidence  A literature review was carried out by the Department of Health Services Research, Cedars-Sinai Health System, Los Angeles, Calif, using the MEDLINE database search for 1990 through April 1998 and updated in November 1998. English-language guidelines, statements, meta-analyses, and overviews on prevention of a first stroke were reviewed. Consensus Process  At the meeting, members of the advisory board identified 6 important stroke risk factors (hypertension, myocardial infarction [MI], atrial fibrillation, diabetes mellitus, blood lipids, asymptomatic carotid artery stenosis), and 4 lifestyle factors (cigarette smoking, alcohol use, physical activity, diet). Conclusions  Several interventions that modify well-documented and treatable cardiovascular and cerebrovascular risk factors can reduce the risk of a first stroke. Good evidence for direct stroke reduction exists for hypertension treatment; using warfarin for patients after MI who have atrial fibrillation, decreased left ventricular ejection fraction, or left ventricular thrombus; using 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors for patients after MI; using warfarin for patients with atrial fibrillation and specific risk factors; and performing carotid endarterectomy for patients with stenosis of at least 60%. Observational studies support the role of modifying lifestyle-related risk factors (eg, smoking, alcohol use, physical activity, diet) in stroke prevention. Measures to help patients improve adherence are an important component of a stroke prevention plan.      

Metabolic effects of pivalate in isolated rat hepatocytes

Pivalate (trimethylacetic acid) administration in humans or rat has been reported to cause metabolic changes and increased urinary carnitine excretion secondary to pivaloylcarnitine generation. As pivaloylcarnitine formation is dependent on intracellular activation of pivalate, the effects of pivalate on cellular coenzyme A and acyl-CoA contents and oxidative metabolism were defined using isolated rat hepatocytes. During incubations with pivalate (1.0 mM), hepatocyte coenzyme A content fell to less than 0.05 nmol/10(6) cells (vs 0.97 nmol/10(6) cells in the absence of pivalate) as pivaloyl-CoA accumulated. Pivalate (5 mM) inhibited 14CO2 generation from 10 mM [1-14C]pyruvate by 34%, but had no effect on 0.8 mM [1-14C]palmitate oxidation. Pivaloyl-CoA was a substrate for hepatocyte carnitine acyltransferase activity, but supported acylcarnitine formation at rates only 10-20% of those observed with equimolar acetyl-CoA or isovaleryl-CoA as substrates. Thus, hepatocytes activate pivalate to pivaloyl-CoA, which can then be used as a substrate for pivaloylcarnitine formation. The sequestration of hepatocyte coenzyme A as pivaloyl-CoA is associated with inhibition of pyruvate oxidation. As with other organic carboxylic acids, activation of pivalate to the coenzyme A thioester is an important aspect in the biochemical toxicology of the compound.