Statins, risk of dementia, and cognitive function: secondary analysis of the ginkgo evaluation of memory study.

BACKGROUND: Lipid-lowering medications (LLMs) and especially statin drugs can delay cognitive decline and dementia onset in individuals with and without mild cognitive impairment (MCI) at baseline. METHODS: A longitudinal, observational study was conducted of 3069 cognitively healthy elderly patients (≥75 years of age) who were enrolled in the Ginkgo Evaluation of Memory Study. The primary outcome measure was the time to adjudicated all-cause dementia and Alzheimer dementia (AD). The secondary outcome measure was the change in global cognitive function over time measured by scores from the Modified Mini-Mental State Exam (3MSE) and the cognitive subscale of the AD Assessment Scale (ADAS-Cog). RESULTS: Among participants without MCI at baseline, the current use of statins was consistently associated with a reduced risk of all-cause dementia (hazard ratio [HR], 0.79; 95% confidence interval [95% CI], 0.65-0.96; P = .021) and AD (HR, 0.57; 95% CI, 0.39-0.85; P = .005). In participants who initiated statin therapy, lipophilic statins tended to reduce dementia risk more than nonlipophilic agents. In contrast, there was no significant association between LLM use (including statins), dementia onset, or cognitive decline in individuals with baseline MCI. However, in individuals without MCI at baseline, there was a trend for a neuroprotective effect of statins on cognitive decline. CONCLUSIONS: Statins may slow the rate of cognitive decline and delay the onset of AD and all-cause dementia in cognitively healthy elderly individuals, whereas individuals with MCI may not have comparable cognitive protection from these agents. However, the results from this observational study need to be interpreted with caution and will require confirmation by randomized clinical trials stratifying treatment groups based on MCI status at baseline.

Assessment of pre- and post-methionine load homocysteine for prediction of recurrent stroke and coronary artery disease in the Vitamin Intervention for Stroke Prevention Trial.

Methionine (Met) loading increases total plasma homocysteine (tHcy) and assesses homocysteine metabolism. We tested the hypothesis that pre- or post-Met tHcy will predict recurrent stroke or coronary artery disease (CAD) in a subgroup analysis of the Vitamin Intervention for Stroke Prevention (VISP) trial. VISP subjects with non-disabling stroke underwent measurement of tHcy at baseline (fasting pre- and post-Met load) and were randomized to high/low-dose B-vitamin therapy for prevention of recurrent stroke or CAD. In the sample cohort of 2124 subjects, mean+/-S.D. tHcy levels in micromol/l were pre-Met 13.2+/-4.3, post-Met 30.4+/-9.76, and pre/post-Met Delta 17.1+/-8.3. The hazard ratio (HR) for recurrent stroke was 1.16 (p=0.026) for 1 S.D. higher pre-Met tHcy and 1.15 (p=0.054) for 1 S.D. higher post-Met tHcy. For CAD, the HR for 1 S.D. higher pre-Met tHcy was 1.27 (p=0.001) and was 1.00 (p=0.99) for post-Met tHcy. In survival analyses using pre- or post-Met as covariates, the coefficient of pre/post-Met Delta was not significant for stroke and was only marginally significant for CAD (p<0.08), but was negative. We conclude that fasting, pre-Met tHcy is as effective as post-Met tHcy or pre/post-Met Delta in predicting the risk for stroke and CAD.

Association of diabetes, homocysteine, and HDL with cognition and disability after stroke.

OBJECTIVE: To delineate factors associated with cognitive function following stroke and test the hypothesis that vascular risk factors associated with oxidative stress impair recovery. METHOD: We performed a post hoc analysis of the extensive longitudinal database from the 3,680 subjects (over 35 years old) entered between 1996 and 2003 into the Vitamin Intervention for Stroke Prevention trial using a linear mixed effects model. The primary outcome variables were scores on the Mini-Mental State Examination (MMSE) and modified Rankin Scale (mRS). RESULTS: MMSE and mRS gradually improved during the 2-year follow-up period. Increased age and nonwhite race, recurrent stroke, diabetes mellitus, left hemisphere cortical lesions, and values of high-density lipoprotein and homocysteine were independent predictors of less successful cognitive recovery. A strong interaction between homocysteine and age indicated a threshold effect beginning in the late 50s. No vitamin treatment effects were identified. Similar factors were identified for recovery of disability as assessed by the mRS, although there were qualitative and quantitative differences. CONCLUSIONS: The finding that diabetes, high-density lipoprotein, and homocysteine predict poorer cognitive function and greater disability after stroke is consistent with the hypothesis that metabolic stress plays a significant role in the poststroke period.

Development, validation, and application of a microsimulation model to predict stroke and mortality in medically managed asymptomatic patients with significant carotid artery stenosis.

OBJECTIVE: To develop a model to predict stroke-free survival and mortality over a multiyear time frame for a trial-excluded population of medically managed asymptomatic patients with significant carotid artery stenosis. METHODS: We calibrated, validated, and applied a Monte Carlo microsimulation model. For calibration we adjusted general-population mortality and stroke risks to capture these risks specific to asymptomatic carotid stenosis patients. For validation, we compared model-predicted and actual stroke-free survival curves and stroke counts from a population of comparable patients. For application, the validated model predicted stroke-free survival for a hypothetical medically managed arm of a recent single-arm carotid revascularization trial. RESULTS: For each month in the 60-month time frame, the model-predicted and actual calibration trial stroke-free survival curves were not statistically different (P > 0.62). In validation, the calibrated model's stroke-free survival curvematched the actual curve from an independent population; beyond 24 months, the model-predicted and actual curves were not statistically different (P > 0.32). We also compared model-predicted and actual number of strokes from the independent trial. The model predicted 187.25 strokes (95% confidence interval 161.49-213.01), while the actual number was 171.6, within 1.22 standard deviations of the simulated mean. CONCLUSIONS: Given the absence of medically managed populations in recent carotid stenosis trials, our model can estimate stroke-free survival and mortality data for these patients. The model may also estimate the effectiveness of novel medical and procedural therapies for stroke prevention. These effectiveness estimates can inform the development of policies, guidelines, or cost-effectiveness analyses when only single-arm trial data exist.

A pianist's recovery from stroke.

OBJECTIVE: To determine alternative neural pathways for restitution of piano playing after right hemispheric infarction causing left arm and hand paralysis. DESIGN: Case report testing coordinated bimanual skills using structured motor skills tests and neuroimaging. SETTING: A professional pianist sustained a lacunar infarction in the posterior limb of his right internal capsule, which resulted in left hemiparesis with immobilized left-hand and -finger movements persisting for 13 weeks. After 6 months, he had recovered bimanual coordinated piano skills by "ignoring" his left hand while concentrating or discussing subjects other than music while playing. PATIENT: A 63-year-old, male professional pianist. INTERVENTION: Detailed neurological examination including computed cranial tomography, functional magnetic resonance imaging, and positron emission tomography. RESULTS: Functional magnetic resonance imaging activation patterns correlated with rapid movements of fingers in each hand separately and together demonstrating that subcortical and cerebellar pathways were activated during skilled motor function of his left hand. Contralateral cerebral and cerebellar activation occurred with both left- and right-hand movements. During tapping of the left fingers, there was bilateral cerebellar, parietal, and left premotor strip and left thalamic activation. CONCLUSION: Patterns of activation relate to task performance and they are not similar to subjects engaged in simpler tasks such as finger opposition.

The changing risk factor profile of participants enrolled in a secondary stroke prevention trial: Vitamin intervention for stroke prevention.

OBJECTIVE: To determine if the stroke risk factor profile of participants in a large, multicenter secondary stroke prevention trial changed over the recruitment period. METHODS: The 3,680 participants in the Vitamin Intervention for Stroke Prevention (VISP) were categorized into four groups by enrollment date. Baseline patient characteristics and stroke risk factors were compared across groups. RESULTS: Hypertension and hypercholesterolemia management improved but prevalence of three major stroke risk factors did not change. Patients enrolled later had better Mini-Mental State and lower NIH Stroke Scale scores, higher multivitamin use, lower prevalence of cortical infarctions, cardiac symptoms and prior stroke, and lower serum creatinine levels. CONCLUSIONS: Those participants enrolled in the later recruitment periods had a different risk factor profile and risk factors were managed differently compared to those enrolled earlier.

Screening for high-grade carotid stenosis using a portable ultrasonography instrument.

BACKGROUND AND PURPOSE: We investigated the diagnostic performance of a brief Power Doppler Imaging (PDI) screening examination for carotid artery stenoses using a newly developed portable instrument. METHODS: A highly experienced sonographer screened in total 152 carotid arteries by either continuous wave (cw) Doppler (n= 50) or a lightweight (2.4 kg) portable duplex device (n= 102) in a prospective study of 76 high-risk patients. The screening protocols included either spectrum analysis and frequency shift measurement in both internal carotid arteries with cw-Doppler or determination of area and diameter ratios in transverse and longitudinal views of both carotid arteries in B-mode and with PDI, but without velocity measurement. Both protocols were evaluated against a complete routine duplex ultrasonography examination. RESULTS: According to the complete examination, stenoses were <50% in 73 of 102 (71.6%), 50-75% in 19 of 102 (18.6%), 75-95% in 7 of 102 (6.9%), and occluded in 3 of 102 (2.9%) arteries (PDI cohort), and <50% in 39 of 50 (78%), 50-75% in 8 of 50 (16%), 75-95% in 2 of 50 (4%), and occluded in 1 of 50 (2%) artery (cw-Doppler cohort). Mean screening time was 8.8 +/- 2.5 minute (PDI) and 9.4 +/- 2.6 minute (cw-Doppler). For stenoses >75%, A(z) values (area under the receiver operating characteristics curve) were 0.897 for area ratios, 0.843 for diameter ratios (PDI protocol) and 1.0 for the cw-Doppler protocol. CONCLUSIONS: The diagnostic performance of the cw-Doppler protocol was superior to the PDI protocol. Nevertheless, both protocols appear suitable as inexpensive screening strategies to identify subjects with >75% stenosis measured by carotid Doppler ultrasound. However, these preliminary data need further verification.

Plasma total homocysteine levels in stroke patients screened for the vitamin intervention for stroke prevention clinical trial in the era of folate fortification.

Folic acid fortification of grain products was mandated in the USA by January 1998 and in Canada by November 1998. It was hypothesized that screening total plasma homocysteine levels adjusted for age, sex, race and country that were drawn in stroke patients for the Vitamin Intervention for Stroke Prevention trial from 1997 to 2001 would be steady when fortification was completed. Samples were grouped by years 1997/1998, 1999 and 2000/2001, and adjusted means were calculated using a general linear regression model. In 2,612 US and 1,059 Canadian patients, levels showed no consistent trend in the USA alone, while Canadian levels declined (p = 0.06 overall, 0.0003 in the oldest age group). US levels were 0.39 micromol/l (95% CI: -0.08, 0.85) lower than in Canada. Neither fasting nor time since stroke affected the results.

Neural networks for ischemic stroke.

BACKGROUND: To have uniform criteria for evaluating populations for prevalence of transient ischemic attack (TIA)/stroke, validated instruments are necessary for objective assessment and classification. METHODS: Patient responses compatible with symptoms of TIA or ischemic stroke, obtained from participants in a substudy of the Asymptomatic Carotid Atherosclerosis Study, were used to program a neural network for each symptom. Models were designed for rapid classification into 1 of 7 outputs: no event, TIA, or stroke (in left carotid, right carotid, or vertebrobasilar). The networks were then tested by comparing decisions with a validated questionnaire used to access an independent data set of 381 patients. RESULTS: There were 144 patients who reported sudden speech change, 89 with sudden vision loss, 67 with double vision, 189 with sudden numbness, 223 with episodic dizziness, and 108 with paralysis, for a total of 820 reported symptoms among the 381 patients tested. For each category, an equal number of individuals reporting "No" to these phenomena were randomly selected and analyzed. Neural network classification correlated with the diagnoses made by specially trained stroke clinicians (e.g., all who responded "No" were correctly classified as having no neurologic event). Ten symptomatic patients were misclassified, with the most common reason being incomplete data. After adjustment of the network logic, these misclassifications did not recur. CONCLUSION: Computer networks can be trained to produce a rapid and accurate classification of TIA or stroke by vascular distribution, enabling screening of populations for assessment of their incidence and prevalence.

Carotid plaque pathology: thrombosis, ulceration, and stroke pathogenesis.

BACKGROUND AND PURPOSE: To determine the relationship between ulceration, thrombus, and calcification of carotid artery atherosclerotic plaques and symptoms of ipsilateral or contralateral stroke. METHODS: We compared microscopic plaque morphology from patients with and without stroke symptoms ipsilateral or contralateral to the plaque. Plaques were characterized for ulceration, thrombus, and calcification. We analyzed plaques from 241 subjects: 170 patients enrolled in the Asymptomatic Carotid Atherosclerosis Study (ACAS) and 71 patients enrolled in the North American Symptomatic Carotid Endarterectomy Trial (NASCET); 128 subjects had no history of stroke symptoms, 80 subjects had ipsilateral symptoms, and 33 had contralateral symptoms. RESULTS: Plaque ulceration was more common in plaques taken from symptomatic patients than those without symptoms (36% versus 14%; P<0.001); frequency of ulceration was similar for plaques associated with ipsilateral (34%) and contralateral (42%) symptoms. Thrombus was most common in plaques taken from patients with both ipsilateral symptoms and ulceration. The extent of calcification was unassociated with stroke symptoms. CONCLUSIONS: Carotid plaque ulceration and thrombosis are more prevalent in symptomatic patients. Ulceration is more common in symptomatic patients regardless of side of carotid symptoms, whereas thrombus is associated with ipsilateral symptoms and plaque ulceration. Preoperative identification of carotid ulceration and thrombus should lead to greater efficacy of stroke prevention by carotid endarterectomy.

Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial.

CONTEXT: In observational studies, elevated plasma total homocysteine levels have been positively associated with ischemic stroke risk. However the utility of homocysteine-lowering therapy to reduce that risk has not been confirmed by randomized trials. OBJECTIVE: To determine whether high doses of folic acid, pyridoxine (vitamin B6), and cobalamin (vitamin B12), given to lower total homocysteine levels, reduce the risk of recurrent stroke over a 2-year period compared with low doses of these vitamins. DESIGN: Double-blind randomized controlled trial (September 1996-May 2003). SETTING AND PARTICIPANTS: 3680 adults with nondisabling cerebral infarction at 56 university-affiliated hospitals, community hospitals, private neurology practices, and Veterans Affairs medical centers across the United States, Canada, and Scotland. INTERVENTIONS: All participants received best medical and surgical care plus a daily multivitamin containing the US Food and Drug Administration's reference daily intakes of other vitamins; patients were randomly assigned to receive once-daily doses of the high-dose formulation (n = 1827), containing 25 mg of pyridoxine, 0.4 mg of cobalamin, and 2.5 mg of folic acid; or the low-dose formulation (n = 1853), containing 200 microg of pyridoxine, 6 microg of cobalamin and 20 microg of folic acid. MAIN OUTCOME MEASURES: Recurrent cerebral infarction (primary outcome); coronary heart disease (CHD) events and death (secondary outcomes). RESULTS: Mean reduction of total homocysteine was 2 micromol/L greater in the high-dose group than in the low-dose group, but there was no treatment effect on any end point. The unadjusted risk ratio for any stroke, CHD event, or death was 1.0 (95% confidence interval [CI], 0.8-1.1), with chances of an event within 2 years of 18.0% in the high-dose group and 18.6% in the low-dose group. The risk of ischemic stroke within 2 years was 9.2% for the high-dose and 8.8% for the low-dose groups (risk ratio, 1.0; 95% CI, 0.8-1.3) (P =.80 by log-rank test of the primary hypothesis of difference in ischemic stroke between treatment groups). There was a persistent and graded association between baseline total homocysteine level and outcomes. A 3- micromol/L lower total homocysteine level was associated with a 10% lower risk of stroke (P =.05), a 26% lower risk of CHD events (P<.001), and a 16% lower risk of death (P =.001) in the low-dose group and a nonsignificantly lower risk in the high-dose group by 2% for stroke, 7% for CHD events, and 7% for death. CONCLUSIONS: In this trial, moderate reduction of total homocysteine after nondisabling cerebral infarction had no effect on vascular outcomes during the 2 years of follow-up. However, the consistent findings of an association of total homocysteine with vascular risk suggests that further exploration of the hypothesis is warranted and longer trials in different populations with elevated total homocysteine may be necessary.

Association between symptoms reported in a population questionnaire and future ischemic stroke: the ARIC study.

The association between computer diagnosis derived from a symptom questionnaire and onset of first hospitalized ischemic stroke during follow-up for up to 11 years has been assessed for 11,804 participants in the Atherosclerosis Risk in Communities Study who had no baseline history of stroke. Of these participants, 578 reported prior positive transient ischemic attack/stroke symptoms, and 265 strokes occurred during the years 1987-1998. Adjusted for age, locale, sex, and race, persons with self-reported baseline symptoms had 2.8 times the hazard rate for incident ischemic stroke of those without symptoms, with 95% confidence interval 1.9-4.1. Greater relative risk was found among younger individuals, women, African-Americans, persons not current smokers, and those with lower white blood cell count.

Progressive cognitive impairment after stroke.

OBJECTIVE: We examined the putative relationship between stroke and cognitive function in the population-based prospective cohort of the Cardiovascular Health Study (CHS). METHODS: Of the 5888 participants of the CHS aged 65 years or older, there were 5364 with more than one modified mini-mental (3MS) examination between 1992 and 1998. To determine the effect of baseline stroke before first and subsequent (stroke between two consecutive examinations) 3MS examination on cognitive function, linear regression models were computed with potential confounders entered as additional independent variables. Stroke was divided into right and left hemispheres or posterior circulation on the basis of the clinical and/or imaging information by the hospital that treated the event and subsequent adjudication by CHS committee. RESULTS: Participants with baseline stroke had an average 3MS decline of 1.2 (95% confidence interval [CI]: -0.7 - -1.7) points per year more than those without one. Those with a history of subsequent stroke had an average first year 3MS decline of 6.2 (CI -8.7 - -3.7) for left hemisphere, 3.5 (CI -5.3 - -1.8) for right hemisphere, and 1.1 (CI -3.9 - 1.6) for posterior circulation more than those without stroke. The effect of stroke on the rate of cognitive decline appeared to ameliorate after the first year (test for linear trend among those with stroke, P = .003). CONCLUSION: Results from this prospective population-based data study show that stroke in the left hemisphere results in a more pronounced decline in cognition than that in the right hemisphere and that cognitive loss because of stroke appears to attenuate over time, perhaps as a result of relearning.

Vitamin intervention for stroke prevention.

Vitamin Intervention for Stroke Prevention (VISP) is designed to determine whether the utilization of folic acid, vitamins B(6) and B(12), in addition to other risk factor reducing measures, have a demonstrable effect on prevention of recurrent stroke. The entry criteria are a first-ever nondisabling stroke, the patient signs informed consent with willingness to participate and randomization to a high- or low-dose vitamin intervention regimen. Case acquisition of 3,688 individuals has been completed, half in the high-dose and the other half in the low-dose intervention arm. Follow-up is in progress and the end results are expected within the year. The Vitamins to Prevent Stroke (VITATOPS) is a parallel study based in Australia with similar goals, and, hopefully, the data from the two will be comparable and supportive.