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Background: The Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. Methods and results: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012–2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P

Low Gray-Scale Median (GSM) index is an ultrasonographic parameter of soft, lipid rich plaque morphology that has been associated with stroke and cardiovascular disease (CVD). We sought to explore the contribution of the modifiable and not-modifiable cardiovascular risk factors (RFs) to vulnerable plaque morphology measured by the low GSM index. A total of 1,030 stroke-free community dwelling individuals with carotid plaques present (mean age, 71.8 ± 9.1; 58% women; 56% Hispanic, 20% Non-Hispanic Black, 22% Non-Hispanic White) were assessed for minimum GSM (min GSM) using high-resolution B-mode carotid ultrasound. Multiple linear regression models were used to evaluate the association between RFs and minGSM after adjusting for sociodemographic characteristics. Within an individual, median plaque number was 2 (IQR: 1-3) and mean plaque number 2.3 (SD: 1.4). Mean minGSM was 78.4 ± 28.7 (IQR: 56-96), 76.3 ± 28.8 in men and 80 ± 28.5 in women; 78.7 ± 29.3 in Hispanics participants, 78.5 ± 27.2 in Non-Hispanic Black participants, and 78.2 ± 29 in Non-Hispanic white participants. In multivariable adjusted model, male sex (β = -5.78, p = 0.007), obesity BMI (β = -6.92, p = 0.01), and greater levels of fasting glucose (β = -8.02, p = 0.02) and LDL dyslipidemia (β = -6.64, p = 0.005) were positively associated with lower minGSM, while presence of glucose lowering medication resulted in a significant inverse association (β = 7.68, p = 0.04). Interaction (with p for interaction <0.1) and stratification analyses showed that effect of age on minGSM was stronger in men (β = -0.44, p = 0.03) than in women (β = -0.20, p = 0.18), and in individuals not taking glucose lowering medication (β = -0.33, p = 0.009). Our study has demonstrated an important contribution of glycemic and lipid metabolism to vulnerable, low density or echolucent plaque morphology, especially among men and suggested that use of glucose lowering medication was associated with more fibrose-stable plaque phenotype (greater GSM). Further research is needed to evaluate effects of medical therapies in individuals with vulnerable, low density, non-stenotic carotid plaques and how these effects translate to prevention of cerebrovascular disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Della-Morte, Dong, Crisby, Gardener, Cabral, Elkind, Gutierrez, Sacco and Rundek.)

Aims: The objective was to evaluate the clinical characteristics, management and two-year outcomes of patients with newly diagnosed non-valvular atrial fibrillation at risk for stroke in Nordic countries., Methods: We examined the baseline characteristics, antithrombotic treatment, and two-year clinical outcomes of patients from four Nordic countries., Results: A total of 52,080 patients were enrolled in the GARFIELD-AF. Out of 29,908 European patients, 2,396 were recruited from Nordic countries. The use of oral anticoagulants, alone or in combination with antiplatelet (AP), was higher in Nordic patients in all CHA 2 DS 2 -VASc categories: 0-1 (72.8% vs 60.3%), 2-3 (78.7% vs 72.9%) and ≥4 (79.2% vs 74.1%). In Nordic patients, NOAC ± AP was more frequently prescribed (32.0% vs 27.7%) and AP monotherapy was less often prescribed (10.4% vs 18.2%) when compared with Non-Nordic European patients. The rates (per 100 patient years) of all-cause mortality and non-haemorrhagic stroke/systemic embolism (SE) were similar in Nordic and Non-Nordic European patients [3.63 (3.11-4.23) vs 4.08 (3.91-4.26), p value = .147] and [0.98 (0.73-1.32) vs 1.02 (0.93-1.11), p value = .819], while major bleeding was significantly higher [1.66 (1.32-2.09) vs 1.01 (0.93-1.10), p value < .001]., Conclusion: Nordic patients had significantly higher major bleeding than Non-Nordic-European patients. In contrast, rates of all-cause mortality and non-haemorrhagic stroke/SE were comparable., Clinical Trial Registration: Unique identifier: NCT01090362. URL: http://www.clinicaltrials.gov., Key Message: Nordic countries had significantly higher major bleeding than Non-Nordic-European countries. Rates of mortality and non-haemorrhagic stroke/SE were similar .

Background: Neurological, visual and hearing deviations have been observed in the offspring of parents with schizophrenia. This study test whether children to parents hospitalized with schizophrenia have increased the likelihood of childhood neurological disorder., Methods: Among all parents in Sweden born 1950-1985 and with offspring born 1968-2002: 7107 children with a parent hospitalized for schizophrenia were compared to 172 982 children with no parents hospitalized for schizophrenia or major depression, as well as to 32 494 children with a parent hospitalized for major depression as a control population with another severe psychiatric outcome. We estimated relative risks (RR) and two-sided 95% confidence intervals calculated from Poisson regression., Results: Children to parents with schizophrenia were more likely than controls to have been hospitalized before the age of 10 with a diagnosis of cerebral palsy, RR = 1.76 (95% CI: 1.15-2.69); epilepsy, RR = 1.78 (95% CI: 1.33-2.40), combined neurological disease, RR = 1.33 (95% CI: 1.11-1.60) and certain diseases of the eye, RR = 1.92 (95% CI: 1.17-3.15) and ear, RR = 1.18 (95% CI: 1.05-1.32). Similar disease-risk-pattern was found for children to parents hospitalized with a diagnosis of major depression. A specific risk increase for strabismus RR = 1.21 (95%CI: 1.05-1.40) was found for off-spring with parental depression., Conclusions: Compared with children to healthy parents, children to parents with schizophrenia have increased risk of a variety of neurological disorders as well as visual and hearing disorders at an early age. The risk increase was not specific to schizophrenia but was also seen in children to parents with a diagnosis of major depression.

Background: Physical activity plays a pivotal role in the development of disability and may modify the negative effect of vascular risk factors on progression of both cardio and cerebrovascular disorders. The aim of this study was to evaluate the activity level in people with age-related white matter changes as identified on magnetic resonance imaging (MRI) in relation to motor performance, cognition and perceived health., Methods: Data came from the first year follow up of one participating centers of the LADIS study. Fifty one subjects were first enrolled in the study. Complete first year follow up data was available for 41 subjects. Information on comorbidity, physical activity level, physical function, cognition, level of white matter changes and perceived health was collected. Physical activity level was classified with a yes or no question and with the Frenchay Activities Index (FAI)., Results: Only 36% of the subjects in this study were physically active according to the yes/no question. 27.5% of the subjects were active according to the FAI score which evaluates the everyday activities. Being active discriminated subjects with better physical function. Subjects active according to the FAI score had a higher cognitive level (p ≤ 0.01), lower comorbidity (p = 0.02) and performed better on all motor function tasks as assessed by walking speed (p ≤ 0.01) and the Short Physical Performance battery (SPPB) (p ≤ 0.01)., Conclusions: Being physically active seems to be a long term protective factor. In our study, the majority of subjects with Age Related White Mattter Changes (ARWMC) with no or mild Instrumental Activity of Daily Living (IADL) disability did not attain recommended level of activity at first year follow up. Whether or not increasing physical activity may slow down cognitive decline and lessen development of disability in physically inactive subjects with manifest ARWC remains to be studied., Trial Registration: not applicable.

Background: Oropharyngeal dysphagia is one of the major complications of stroke and a risk factor for malnutrition and prolonged in-hospital stay., Objective: The overall aim was to describe to what extent nutritional assessments (i.e. BMI kg/m(2), eating problem, and weight loss) were performed and documented in the records of older stroke patients treated with enteral nutrition by percutaneous endoscopic gastrostomy (PEG). A secondary aim was to identify documented post-procedural complications after PEG insertion during hospital stay., Design: The study is retrospective. Data were collected from records of 161 stroke patients ≥65 years, who received PEG, admitted to three stroke units during a 4-year period., Results: Mean age of the patients was 82.2 (±7) years, and 86% of the patients were ≥75 years old. On admission, body weight was documented in 50% of the patients and at discharge in 38% of the patients. BMI data were not documented at all at discharge in one of the units. Almost 80% of the patients fulfilled the European Network criteria for multimorbidity. Morbidity and multimorbidity correlated to the length of stay (p<0.0005). Complications were reported in 111 (69%) of the patient records. In 53 patients (33%) more than one complication was reported. A total of 116 pressure ulcers were reported and 30 patients had more than one pressure ulcer. The number of complications was related to weight loss (p=0.046) and BMI change (p=0.018)., Conclusions: Essential information of the patient's nutritional status was poorly recorded which could affect the patient's nutritional treatment during the hospital stay. This study indicates that implementation of guidelines in patients with stroke is needed. The high number of pressure ulcers was an unexpected finding.

Background and Purpose: Recent drug trials have challenged the high-density lipoprotein-cholesterol (HDL-C) antiatherosclerotic hypothesis, suggesting that total level of HDL-C may not be the best target for intervention. HDL-C subfractions may be better markers of vascular risk than total levels of HDL-C. The objective of this cross-sectional study was to investigate the relationship between HDL2-C and HDL3-C fractions and carotid intima-media thickness (cIMT) in the population-based Northern Manhattan Study., Methods: We evaluated 988 stroke-free participants (mean age, 66±8 years; 60% women; 66% Hispanic, and 34% non-Hispanic) with available data on HDL-C subfractions using precipitation method and cIMT assessed by a high-resolution carotid ultrasound. The associations between HDL-C subfractions and cIMT were analyzed by multiple linear regression models., Results: The mean HDL2-C was 14±8 mg/dL, HDL3-C 32±8 mg/dL, and the mean total HDL-C was 46±14 mg/dL. The mean cIMT was 0.90±0.08 mm. After controlling for demographics and vascular risk factors, HDL2-C and total HDL-C were inversely associated with cIMT (per 2 SDs, β=-0.017, P=0.001 and β=-0.012, P=0.03, respectively). The same inverse association was more pronounced among those with diabetes mellitus (per 2SDs, HDL2-C: β=-0.043, P=0.003 and HDL-C: β=-0.029, P=0.02). HDL3-C was not associated with cIMT., Conclusions: HDL2-C had greater effect on cIMT than HDL3-C in this large urban population. The effect of HDL2-C was especially pronounced among individuals with diabetes mellitus. More research is needed to determine antiatherosclerotic effects of HDL-C subfractions and their clinical relevance., (© 2016 American Heart Association, Inc.)

Objective: Carotid intima-media thickness (cIMT) and carotid plaque (CP) are proposed biomarkers of subclinical atherosclerosis associated with stroke risk. Whether cIMT and CP are distinct phenotypes or single traits at different stages of atherosclerotic development is unclear. We explored the relationship between these markers in the population-based Northern Manhattan Study., Methods: We used high-resolution ultrasound and validated imaging protocols to study the cross-sectional (N = 1788 stroke-free participants) and prospective relationship (N = 768 with follow-up scan; mean years between examinations = 3.5) between CP and cIMT measured in plaque-free areas., Results: The mean age was 66 ± 9 (40% male, 19% black, 17% white, 61% Hispanic). The mean baseline cIMT was 0.92 ± 0.09 mm, 0.94 ± 0.09 mm among the 58% with prevalent plaque, 0.90 ± 0.08 mm among the 42% without prevalent plaque (p < 0.0001). Each 0.1 mm increase in baseline cIMT was associated with a 1.72-fold increased odds of plaque presence (95%CI = 1.50-1.97), increased plaque thickness (effect on the median = 0.46 mm, p < 0.0001), and increased plaque area (effect on the median = 3.45 mm(2), p < 0.0001), adjusting for demographics and vascular risk factors. Elevated baseline cIMT was associated with an increased risk of new plaque in any location at follow-up, but after adjusting for demographics and vascular risk factors this association was no longer present. No association was observed in carotid segment-specific analyses., Conclusion: Increased cIMT was associated with baseline prevalent plaque but did not predict incident plaque independent of other vascular risk factors. This finding suggests that increased cIMT is not an independent predictor of plaque development although these atherosclerotic phenotypes often coexist and share some common vascular determinants., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Functional deficits seen in several neurodegenerative disorders have been linked with dysfunction in frontostriatal circuits and with associated shape alterations in striatal structures. The severity of visible white matter hyperintensities (WMHs) on magnetic resonance imaging has been found to correlate with poorer performance on measures of gait and balance. This study aimed to determine whether striatal volume and shape changes were correlated with gait dysfunction., Methods: Magnetic resonance imaging scans and clinical gait/balance data (scores from the Short Physical Performance Battery [SPPB]) were sourced from 66 subjects in the previously published LADIS trial, performed in nondisabled individuals older than age 65 years with WMHs at study entry. Data were obtained at study entry and at 3-year follow-up. Caudate nuclei and putamina were manually traced using a previously published method and volumes calculated. The relationships between volume and physical performance on the SPPB were investigated with shape analysis using the spherical harmonic shape description toolkit., Results: There was no correlation between the severity of WMHs and striatal volumes. Caudate nuclei volume correlated with performance on the SPPB at baseline but not at follow-up, with subsequent shape analysis showing left caudate changes occurred in areas corresponding to inputs of the dorsolateral prefrontal, premotor, and motor cortex. There was no correlation between putamen volumes and performance on the SPPB., Conclusion: Disruption in frontostriatal circuits may play a role in mediating poorer physical performance in individuals with WMHs. Striatal volume and shape changes may be suitable biomarkers for functional changes in this population., (Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: We sought to determine the association between cigarette smoking and carotid plaque ultrasound morphology in a multiethnic cohort., Methods: We analyzed 1,743 stroke-free participants (mean age 65.5 ± 8.9 years; 60% women; 18% white, 63% Hispanic, 19% black; 14% current and 38% former smokers, 48% never smoked) from the Northern Manhattan Study using an ultrasound index of plaque echodensity, the Gray-Scale Median (GSM). Echolucent plaque (low GSM) represents soft plaque and echodense (high GSM) more calcified plaque. The mean GSM weighted by plaque area for each plaque was calculated for those with multiple plaques. Quintiles of GSM were compared to no plaque. Multinomial logistic regression models were used to assess associations of cigarette smoking with GSM, adjusting for demographics and vascular risk factors., Results: Among subjects with carotid plaque (58%), the mean GSM scores for quintiles 1-5 were 48, 72, 90, 105, and 128, respectively. Current smokers had over a two fold increased risk of having GSM in quintile 1 (odds ratio (OR) = 2.17; 95% confidence interval (CI), 1.34-3.52), quintile 2 (OR = 2.33; 95% CI, 1.42-3.83), quintile 4 (OR = 2.05; 95% CI, 1.19-3.51), and quintile 5 (OR = 2.13; 95% CI, 1.27-3.56) but not in quintile 3 (OR = 1.18; 95% CI, 0.67-2.10) as compared to never smokers in fully adjusted models. Former smokers had increased risk in quintile 2 (OR = 1.46; 95% CI, 1.00-2.12), quintile 3 (OR = 1.56; 95% CI, 1.09-2.24), quintile 4 (OR = 1.66; 95% CI, 1.13-2.42), and quintile 5 (OR = 1.73; 95% CI, 1.19-2.51), but not in quintile 1 (OR = 1.05; 95% CI, 0.72-1.55)., Conclusions: A nonlinear, V-shaped-like relationship between current cigarette smoking and plaque echodensity was observed. Former smokers were at the highest risk for plaques in high GSM quintiles. Thus, current smokers were more likely to have either soft or calcified plaques and former smokers were at greater risk of having only echodense plaques when compared to those who have never smoked. Further research is needed to determine if plaque morphology mediates an association between smoking and clinical vascular events., (© 2015 S. Karger AG, Basel.)

Objective: The objective of this cross-sectional analysis was to investigate the relation between two major high-density lipoprotein cholesterol (HDL-C) subfractions (HDL2-C and HDL3-C) and carotid plaque in a population based cohort., Methods: We evaluated 988 stroke-free participants (mean age 66 ± 8 years; 40% men; 66% Hispanic and 34% Non-Hispanic) with available data on HDL subfractions using precipitation method and carotid plaque area and thickness assessed by a high-resolution 2D ultrasound. The associations between HDL-C subfractions and plaque measurements were analyzed by quantile regression., Results: Plaque was present in 56% of the study population. Among those with plaque, the mean ± SD plaque area was 19.40 ± 20.46 mm² and thickness 2.30 ± 4.45 mm. The mean ± SD total HDL-C was 46 ± 14 mg/dl, HDL2-C 14 ± 8 mg/dl, and HDL3-C 32 ± 8 mg/dl. After adjusting for demographics and vascular risk factors, there was an inverse association between HDL3-C and plaque area (per mg/dl: beta = -0.26 at the 75th percentile, p = 0.001 and beta = -0.32 at the 90th percentile, p = 0.02). A positive association was observed between HDL2-C and plaque thickness (per mg/dl; beta = 0.02 at the 90% percentile, p = 0.003). HDL-C was associated with plaque area (per mg/dl: beta = -0.18 at the 90th percentile, p = 0.01), but only among Hispanics., Conclusion: In our cohort we observed an inverse association between HDL3-C and plaque area and a positive association between HDL2-C and plaque thickness. HDL-C subfractions may have different contributions to the risk of vascular disease. More studies are needed to fully elucidate HDL-C anti-atherosclerotic functions in order to improve HDL-based treatments in prevention of vascular disease and stroke., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

We determined whether plasma levels of circulating oxidized low-density lipoprotein (LDL; E06), immunoglobulin (Ig) G, and IgM autoantibodies binding to malonyldialdehyde-modified LDL (MDA-LDL) may predict cardiovascular events (CVEs). Patients (n=123) with a previous myocardial infarction (MI) were included. The primary end point was defined as any of the following: cardiovascular death from any cause, nonfatal reinfarction or stroke, percutaneous coronary intervention, coronary artery bypass grafting, and hospitalization due to angina pectoris. There were 43 CVEs during the follow-up period of 8.4±3.5 years. There was no significant difference in the levels of E06 and MDA-LDL IgG between the CVE and the event-free group. However, MDA-LDL IgM levels were significantly lower in patients in the CVE group (9524±6326 relative light unit [RLU]) compared with the event-free (10,975±5398 RLU) group (P=.04). In conclusion, levels of MDA-LDL IgM were associated with an increased risk of CVE in patients with a previous MI., (© The Author(s) 2013.)

Background: Angiogenesis is usually driven by inflammation. Matrix metalloproteinases MMP-3 and MMP-9 and tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 are implicated in vascular remodeling. TIMP-2 exhibits antiangiogenic properties. Statins show benefits that are additional to lipid lowering including pro- and antiangiogenic properties. Atherosclerotic lesions in the coronary arteries have been well studied, but less is known about the fine terminal branches of the myocardial vasculature., Methods: To examine this, we studied rosuvastatin (RSV) treatment in ApoE knockout (ApoE(-/-)) mice fed a high cholesterol (HC) diet. Hearts from ApoE(-/-) mice on a normal diet, HC diet and HC diet with RSV were harvested to determine MMP-3, MMP-9, TIMP-1, TIMP-2, vascular endothelial growth factor (VEGF)-A and estrogen receptor-α (ER-α) mRNA., Results: RSV inhibited TIMP-1 and TIMP-2 expression and enhanced myocardial VEGF-A and ER-α expression, independently of plasma lipid level changes, but had no effect on MMP-3 and MMP-9 expression., Conclusions: These modulations of TIMPs, VEGF and ER-α expression induced by RSV may act as local stimulating factors for arteriolar growth in the myocardium., (© 2014 S. Karger AG, Basel.)

White matter changes (WMC) are common magnetic resonance imaging (MRI) findings, particularly in the elderly. Recent studies such as the Leukoaraiosis and Disability Study (LADIS) have found that WMC relate to adverse outcomes including cognitive impairment, depression, disability, unsteadiness and falls in cross-sectional and follow-up studies. Frontostriatal (or frontosubcortical) brain circuits may serve many of these functions, with the caudate nuclei playing a role in convergence of cognitive functions. This study aimed to determine whether reduced caudate volume relates to cognitive functions (executive functions, memory functions and speed of processing) and WMC. We determined caudate nuclei volumes, through manual tracing, on a subgroup of the LADIS study (n=66) from four centres with baseline and 3-year follow-up MRI scans. Regression analysis was used to assess relationships between caudate volume, cognitive function and WMC. Severity of WMC did not relate to caudate volume. Smaller caudate volumes were significantly associated with poorer executive functioning at baseline and at 3 years, but were not associated with scores of memory or speed of processing. Thus, in patients with WMC, a surrogate of small vessel disease, caudate atrophy relates to the dysexecutive syndrome, supporting the role of caudate as an important part of the frontostriatal circuit., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Eating disorders are prevalent, serious conditions that affect mainly young women. An early and enduring sign of anorexia is amenorrhea. There is no evidence for benefits of hormone therapy in patients with anorexia; however, hormone medication and oral contraceptives are frequently prescribed for young women with anorexia as a prevention against and treatment for low bone mineral density. The use of estrogens may create a false picture indicating that the skeleton is being protected against osteoporosis. Thus the motivation to regain weight, and adhere to treatment of the eating disorder in itself, may be reduced. The most important intervention is to restore the menstrual periods through increased nutrition. Hormone and oral contraceptive therapy should not be prescribed for young women with amenorrhea and concurrent eating disorders., (© 2013 Nordic Federation of Societies of Obstetrics and Gynecology.)

Background: Population-based data on serum adiponectin levels, an adipocytokine secreted from adipose tissue, are lacking, particularly across race-ethnic groups. Studies have suggested an inverse association between adiponectin and vascular risk factors, but data are limited and inconsistent. We examined the cross-sectional association between adiponectin, vascular risk factors and race-ethnicity in the population-based Northern Manhattan Study (NOMAS)., Methods: Blood samples, anthropomorphics, and vascular risk factors were collected at baseline. Multivariable linear regression analysis was conducted with log-transformed adiponectin as the dependent variable., Results: Adiponectin was measured among 2900 participants (age 69±10 years, body mass index (BMI) 28.0±5.6, 37% male, 21% white, 53% Hispanic, 24% black). The mean adiponectin was 11.4±6.2 μg/mL (median=9.8, range=2.1-53.3). After multivariable adjustment, adiponectin levels were greatest among whites, followed by Hispanics, and lowest among blacks. Lower adiponectin levels were observed in participants with the following characteristics: Male, former smoking, hypertension, diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), metabolic syndrome, moderate alcohol use, elevated waist circumference, BMI, estimated glomerular filtration rate (eGFR), triglycerides, low-density lipoprotein cholesterol (LDL-C), lower high-density lipoprotein cholesterol (HDL-C), and younger age. Obesity was a stronger risk factor for decreased adiponectin among blacks than among whites or Hispanics. The associations for several vascular risk factors, including hypertension, triglycerides, and low HDL-C, with low adiponectin were stronger among individuals who were not obese than among those who were obese., Conclusions: Adiponectin levels were lower among blacks and Hispanics and among those with various vascular risk factors, and greater with older age. The association between BMI and adiponectin varied across race-ethnic groups. Investigation of whether differences in body fat distribution may explain race-ethnic differences in adiponectin is needed.

Both cerebrovascular disease (CVD) and depression are common conditions in the elderly, and there is emerging evidence of a bi-directional relationship: 1) depression can cause CVD and stroke, transient ischemic attack; and 2) subcortical CVD are associated with increased risk for depression. The frequency of poststroke depression is highest during the first month after the stroke, but remains high even after several years. Depression is associated with poorer functional prognosis and higher mortality after stroke. There is good evidence that severity of functional impairment, high neuroticism, low social support as well as genetic factors are associated with an increased risk for post-stroke depression. Deep white matter lesions are the most consistent imaging correlate of depression. Potential mechanisms mediating the association between depression and CVD are neuroinflammation and HPA-axis activation, fronto-subcortical circuit lesions, and serotonergic dysfunction. Antidepressants have demonstrated effect on poststroke depression in meta-analyses, and such drugs as well as vitamin B can reduce the incidence of depression in stroke survivors. In addition, serotonergic drugs may strengthen poststroke motor and cognitive recovery, potentially through restorative mechanisms. Psychotherapeutic strategies such as problem-solving therapy seem to be effective. There is emerging evidence that treatment of cardiovascular disease and risk-factors can reduce the risk for late-life depression, but more studies are needed to test this hypothesis.

Background and Purpose: Adiponectin is an insulin-sensitizing plasma protein expressed in adipose tissue and suggested to play a role in atherosclerosis and cardiovascular disease. Data are lacking on the relationship between adiponectin and carotid intima-media thickness (IMT) in ethnically heterogeneous populations. We examined the relationship between adiponectin and IMT, a marker of atherosclerosis, in a multiethnic cohort study of stroke risk factors., Methods: Participants were from the Northern Manhattan Study (N=1522, mean age 66±9 years, 60% female, 20% black, 18% white, 60% Hispanic). Adiponectin was measured from baseline plasma samples and IMT was assessed by high-resolution B-mode carotid ultrasound. Regression models were used to examine the association between adiponectin, assessed continuously and in quartiles, and IMT controlling for demographics and vascular risk factors., Results: The mean adiponectin level was 10.3±5.2 μg/mL (median, 9.2 μg/mL; range, 2.3-53.3 μg/mL), and the mean IMT was 0.91±0.08 mm. Adiponectin was inversely associated with IMT, even after controlling for demographics and vascular risk factors. Individuals in the first quartile of adiponectin had mean IMT that was on average 0.02 mm greater than those in the top quartile. The relationship between adiponectin and IMT appeared to be stronger among those with diabetes., Conclusions: Our findings suggest that low adiponectin is associated with increased IMT in a multiethnic cohort and support a protective role for adiponectin in atherosclerosis.

We have previously shown that a high cholesterol (HC) diet results in increases in microglia load and levels of the pro-inflammatory cytokine interleukin-6 (IL-6) in the brains of wild type (WT) and apolipoprotein E knockout (ApoE-/-) mice. In the present investigation, we analyzed whether treatment with rosuvastatin, an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, would prevent the increases in inflammatory microglia and IL-6 levels in the brain and plasma of WT and ApoE-/- mice. We report that a HC diet resulted in an increased microglia load in the brains of WT and ApoE-/- mice, in support of our previous study. Treatment with rosuvastatin significantly decreased the microglia load in the brains of WT and ApoE-/- mice on a HC diet. Rosuvastatin treatment resulted in lowered plasma IL-6 levels in WT mice on a HC diet. However, in the present study the number of IL-6 positive cells in the brain was not significantly affected by a HC diet. A recent clinical study has shown that rosuvastatin reduces risk of ischemic stroke in patients with high plasma levels of the inflammatory marker C-reactive protein by 50%. The results from our study show that rosuvastatin reduces inflammatory cells in the brain. This finding is essential for furthering the prevention and treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and stroke., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background and Purpose: Cerebral White matter changes (WMC) are a frequent finding on CT and MRI scans of elderly individuals, particularly in those with vascular risk factors, cerberovascular disease, and cognitive impairment., Methods: 56 subjects were included in the study after the review of reports of more than 200 consecutive brain Computerized Tomography (CT) and magnetic resonance imaging (MRI) examinations from the out-patient and in-patient units of the Department of Geriatric Medicine at Karolinska University Hospital, Huddinge during 2001-2002. MRI was performed using a 1.5 T system and WMC lesions were graded 1-3 using a visual scale. Total-cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL) and triglyceride (TG) levels were determined using enzymatic techniques after 12 hours overnight fasting. Apo E genotyping was performed as described., Results: Low HDL levels were associated with higher severity of WMC on MRI (p=0.002). Subjects with the Apo E4 allele had higher LDL (p=0.02) and apoB levels (p=0.005). The presence of the Apo E4 allele was higher in the group of subjects with severe WMC (grade 3). However, there was no statistically significant group difference in severity of WMC lesions between carriers and non-carriers of Apo E4 allele., Conclusions: Low HDL is strongly associated with adverse coronary and cerebrovascular outcomes. Our results indicate that low HDL levels are also associated with more severe WMC lesions on MRI. Dietary or medical adjustment of HDL levels could have important implications for treatment and prevention of cerebral WMC, cerebrovascular and neurodegenerative diseases such as stroke and dementia.

The processing of the Amyloid Precursor Protein (APP) is a critical event in the formation of amyloid plaques which are composed of the 4kDa amyloid beta-peptide (Abeta). Processing of APP occurs through a non-amyloidogenic pathway, mediated by initial alpha-secretase cleavage or through an amyloidogenic pathway via sequential cleavage by beta- and gamma-secretase enzymes, which produces Abeta peptides. Currently, the diagnosis of probable or possible Alzheimer's disease (AD) is primarily based on neuropsychological and neuroradiological assessment. Recent reports indicate that platelet beta-secretase activity is moderately increased in patients with AD and mild cognitive impairment (MCI). To our knowledge platelet alpha-secretase activity has not yet been explored in this context and estimation of the ratio of the activities of alpha- and beta-secretase in platelets may represent a useful surrogate marker of the balance between the two pathways of APP metabolism and be of importance for the diagnosis of AD. We therefore considered it of interest to develop assays of platelet alpha- and beta-secretase activities suitable for such clinical investigations. Application of these assays to a Swedish population failed to uncover an effect of AD or MCI on individual platelet secretase activities or the secretase ratio. However, we did observe an inverse correlation between plasma triacylglycerol levels and the secretase ratio. The results are discussed in the context of the clinical usefulness of the secretase ratio as a biochemical adjunct to the diagnosis of AD.

The association between C-reactive protein (CRP) and future cardiovascular risk has been of particular interest during recent years. Oxidized low-density lipoprotein (ox-LDL) is another marker linking the immune system with the atherogenic process. The aim of this study was to examine whether ox-LDL and CRP were associated with endothelial function in peripheral resistance arteries. Twenty-five men with a previous hospital-diagnosed myocardial infarction were enrolled in the study. The exclusion criterion was a history of diabetes mellitus. IgG and IgM autoantibodies to malonyldialdehyde low-density lipoprotein (MDA-LDL) and high-sensitivity CRP (hs-CRP) were measured. Flow-mediated dilatation was measured in isolated resistance arteries from subcutaneous fat biopsies. Endothelial function test reflecting the maximum vessel dilatation in male subjects was inversely related to MDA-LDL IgG autoantibody levels (r = -0.6 and P = 0.003). Comparison of hs-CRP levels and of maximum vessel dilatation in males revealed also an inverse relation (r= -0.4 and P = 0.04). In conclusion, a clear correlation exists between flow-mediated dilatation in subcutaneous resistance arteries and plasma levels of MDA-LDL IgG autoantibody and CRP in male patients with coronary heart disease.

Objectives: To investigate, in a cohort of nondisabled elderly people, the association between urinary complaints and severity of age-related white matter changes (ARWMC)., Design: Cross-sectional data analysis from a longitudinal multinational study., Setting: The Leukoaraiosis And DISability Study, assessing ARWMC as an independent predictor of the transition from functional autonomy to disability in elderly subjects., Participants: Six hundred thirty-nine subjects (288 men, 351 women, mean age 74.1+/-5.0) with magnetic resonance imaging (MRI)-detected ARWMC of different severity., Measurements: ARWMC severity was graded on MRI as mild, moderate, and severe (Fazekas scale). MRI assessment also included ARWMC volumetric analysis and the count of infarcts. Urinary complaints (nocturia, urinary frequency, urgency, incontinence) were recorded based on subjects' answers to four questions., Results: In comparing the three ARWMC severity groups, there was a significant difference only in prevalence of urgency, with 16% of subjects in the mild severity group, 17% in the moderate severity group, and 25% in the severe group (P=.03). Adjusting for age, sex, lacunar and nonlacunar infarcts, diabetes mellitus, and use of diuretics, severe ARWMC retained an independent effect in the association with urinary urgency (odds ratio=1.74, 95% confidence interval=1.04-2.90, severe vs mild group). Subjects with urinary urgency also had higher ARWMC volumes (25.2, vs 20.4 mm(3) in those without urinary urgency; P<.001). Urgency was confirmed to be associated with the severe degree of ARWMC, irrespective of complaints of memory, gait disturbances, or history of depression., Conclusion: In a cohort of nondisabled elderly people, severe ARWMC were associated with urinary urgency, independent of other potential confounders and vascular lesions of the brain.

The cholesterol 24-hydroxylase encoded by the gene CYP46 is expressed almost exclusively in central nervous system (CNS) neurons and catalyzes the formation of 24S-hydroxycholesterol (24S-OHC) from cholesterol. This conversion corresponds to a major pathway for excretion of excess cholesterol from the brain. There is a significant flux of another oxysterol, 27-hydroxycholesterol (27-OHC) from the circulation into the brain. Polymorphisms within the CYP46A1 gene have been associated with Alzheimer's disease (AD) incidence. In this study, we examined the effects of 24S-OHC and 27-OHC on the alpha- and beta-secretase activity in the human neuroblastoma cell line SH-SY5Y. Furthermore, we examined the effects of the two oxysterols on the levels of extra- and intracellular proteins of secreted APPalpha (sAPPalpha). Our findings suggest that 24S-OHC may exert a unique modulatory effect on APP processing and that this oxysterol increases the alpha-secretase activity as well as the alpha/beta-secretase activity ratio. The possibility is discussed that the ratio between 24S-OHC and 27-OHC is of importance for the generation of amyloid in the brain.

The influence of a high cholesterol (HC) diet on brain pathology is being recognized increasingly and is of immense interest. Previous findings from our laboratory demonstrated that a high cholesterol diet increases gliosis, astrocytic reactivity and neuroinflammation in both wild type (WT) and apolipoprotein knockout (ApoE-/-) mice. In the present study, we analyzed whether this increase in astrocytic reactivity, monitored by the number of cells in the hippocampus labelled with glial fibrillary acidic protein (GFAP), could be reduced by the use of rosuvastatin, a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase. Furthermore, we studied the effect of rosuvastatin on changes in lipoprotein levels and weight gain, and their correlation to gliosis, in mice fed a high cholesterol diet. A significant increase in weight, total-cholesterol (TC) and low-density lipoprotein (LDL) levels were observed in WT and ApoE-/- mice on a HC diet. The number of GFAP labelled cells was found to be significantly increased in mice on a HC diet and reduced in rosuvastatin-treated WT and ApoE-/- mice on a HC diet. A significant reduction of weight, total-cholesterol and LDL levels was observed in rosuvastatin-treated WTHC mice. Significant correlations were found between changes in body weight, GFAP labelled cells and plasma total-cholesterol levels in WT and ApoE-/- mice. However, the correlations were found to be weaker for the GFAP labelled cells in the ApoE-/- mice. The results indicate that the observed reduction of gliosis by rosuvastatin treatment may be due to mechanisms that are independent of its lipid-lowering effect.

In order to reveal the neuroprotective effects of statins that could be of interest for the prevention and treatment of Alzheimer's disease (AD), we investigated the expression of nicotinic acetylcholine receptors (nAChRs) detected by RT-PCR, the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by colorimetric determination, and the levels of the alpha-form of secreted beta-amyloid precursor protein (alphaAPPs) by Western blotting in neuroblastoma (SH-SY5Y) cells exposed to lovastatin, atorvastatin, rosuvastatin and simvastatin, respectively. The results indicated that all statins studied, both lipophilic and hydrophilic, induced high expression of alpha7 nAChR, decreased cholinesterase activities, and increased alphaAPPs, which suggests that statins might play important neuroprotective roles in AD treatment.

High serum cholesterol is associated with ischemic heart disease. Recent reports also indicate that cholesterol modulates amyloid beta-peptide interactions in the brain. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme involved in cholesterol synthesis. Statin treatment significantly reduces the levels of low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL). In the past decade, cardiovascular mortality and morbidity has been reduced by the use of statins. However, evidence from in vivo and in vitro research has indicated that statins may confer multiple effects because of the inhibition of the production of intermediates in the mevalonate pathway. The aim of this review was to discuss the biological effects of statins on regulation of processes involved in the pathogenesis of dementia.

Inflammation in the central nervous system is an early hallmark of many neurodegenerative diseases including Alzheimer's disease (AD). Recently, increasing evidence suggests that hypercholesterolemia during midlife and abnormalities in the cholesterol metabolism could have an important role in the pathogenesis of AD. In the present study, we have evaluated the effect of high cholesterol (HC) diet on the expression of interleukin-6 (IL-6), a cytokine involved in neurodegeneration, and caspase-1, that is responsible for the cleavage of the precursors of interleukin-1 beta (IL-1 beta) and interleukin-18 (IL-18) in the brain of apolipoprotein E (Apo E) knock-out (KO) and wild type (WT) mice. The density of IL-6-positive cells was increased in the hippocampus (p<0.0001) and the dorsal part of the cortex (p<0.001) of KO and WT mice on HC diet (KOHC and WTHC mice, respectively) compared to KO and WT mice on ND (KOND and WTND mice, respectively). KOHC mice had increased caspase-1 positive cells and staining intensity in the hippocampus in comparison with WTHC mice (p<0.01). In the hippocampus, the density of caspase-1 positive cells was also higher in KOHC compared to KOND mice (p<0.05) and KOHC compared with WTHC mice (p<0.01). There was a major increase in caspase-1 immunoreactivity and cell density in both the dosal part of the cortex (p<0.001) and the lateral part of the cortex (p<0.005) in KO and WT mice on HC diet compared to ND. The findings of the present study indicate that chronic exposure to HC diet increases the expression of the two important inflammatory mediators IL-6 and caspase-1 in the brain of KO and WT mice. In the case of caspase-1, we report a major difference in the effect of HC diet on the KO mice compared to WT mice in the hippocampus. Increased expression of inflammatory mediators involved in neurodegeneration could be a potential mechanism by which hypercholesterolemia and HC diet increase the risk of AD.

We analysed the effects of high cholesterol (HC) intake and reduced apolipoprotein E (apoE) activity on tau phosphorylation and on the activities of the major tau kinases and phosphatases in brains from wild-type and apoE-knockout (apoEKO) mice. We show that HC diet potently induced intraneuronal accumulation of hyperphosphorylated tau in apoEKO mice, as well as upregulation of several tau kinases, without affecting tau phosphatases. Our results suggest an interaction between dietary and genetic factors in the development of tauopathies, which can be relevant in humans, where the apoE4 isoform could have a lack of function as compared to other isoforms.

Objective: Our objective was to assess vascular endothelial function and morphology in resistance vasculature from healthy pre- and postmenopausal women in vitro and to determine potential mechanisms of vascular protection by estrogenic compounds., Methods: Arteries (approximately 220 microm) were dissected from sc fat biopsies obtained from healthy premenopausal and postmenopausal women. Flow-mediated dilatation, agonist-induced endothelium-dependent and -independent relaxation, and myogenic responses to changes in intraluminal pressure were evaluated before and after incubation (3 h) with 17beta-estradiol, propyl pyrazole triol [a selective estrogen receptor-alpha (ERalpha) agonist], raloxifene (a second-generation selective ER modulator), and the phytoestrogen genistein, using pressure myography technique. In addition, endothelial morphology was assessed in arteries from pre- and postmenopausal women, and distribution of ERs within the artery wall from postmenopausal women was evaluated., Results: Functional and morphological disturbances of endothelial function were observed in small arteries from postmenopausal women. Incubation with 17beta-estradiol improved postmenopausal resistance artery function, an effect mimicked by propyl pyrazole triol but not raloxifene or genistein. Immunohistochemical staining revealed similar expression of ERalpha and ERbeta in the smooth muscle of arteries from postmenopausal women; however, ERalpha was dominant in endothelium., Conclusions: The resistance arteries from postmenopausal women show functional and morphological abnormalities. ERalpha may contribute to vascular protection by estrogens in the peripheral resistance circulation in postmenopausal women. Selective ERalpha agonists warrant further investigation as therapeutic agents for prevention of cardiovascular disease in postmenopausal women.

Background and Purpose: On cerebral magnetic resonance imaging (MRI), white matter hyperintensities (WMH) and lacunes are generally viewed as evidence of small vessel disease. The clinical significance of small vessel disease in terms of global cognitive function has as yet not been completely clarified. We investigated the independent contribution of WMH and lacunes to general cognitive function in a group of independently living elderly with varying degrees of small vessel disease., Methods: Data were drawn from the multicenter, multinational Leukokraurosis and Disability (LADIS) study. There were 633 independently living participants. General cognitive function was assessed using the Mini Mental State Examination (MMSE) and the modified Alzheimer Disease Assessment Scale (ADAS). On MRI, WMH was rated as mild, moderate, or severe. Lacunes were rated as none, few (1 to 3), or many (4 or more)., Results: In the basic analysis, increasing severity of both WMH and lacunes was related to deteriorating score on the MMSE and ADAS. When WMH and lacunes were entered simultaneously, both MRI measures remained significantly associated with MMSE score. Increasing severity of WMH remained associated with ADAS score, whereas the association with lacunes became less prominent. These associations were independent of other risk factors for dementia, like education, depression, vascular risk factors, or stroke., Conclusions: We found WMH and lacunes to be independently associated with general cognitive function in a sample of independently living elderly. These results highlight the fact that WMH and lacunes should both be evaluated when assessing small vessel disease in relation to cognitive function.

High serum cholesterol level has been shown as one of the risk factors for Alzheimer's disease (AD), and epidemiological studies indicate that treatment with cholesterol-lowering substances, statins, may provide protection against AD. An acute-phase reaction and inflammation, with increased levels of proinflammatory cytokines, are well known in the AD brain. Notably, there is evidence for antiinflammatory activities of statins, such as reduction in proinflammatory cytokines. Consequently, it is of interest to analyze the effects of statins on microglia, the main source of inflammatory factors in the brain, such as in AD. The aims of this study were to determine the effects of statins (atorvastatin and simvastatin) on microglial cells with regard to the secretion of the inflammatory cytokine interleukin-6 (IL-6) and cell viability after activation of the cells with bacterial lipopolysaccharides (LPS) or beta-amyloid1-40 (Abeta1-40) and in unstimulated cells. Cells of the human microglial cell line CHME-3 and primary cultures of rat neonatal cortical microglia were used. Incubation with LPS or Abeta1-40 induced secretion of IL-6, and Abeta1-40, but not LPS, reduced cell viability. Both atorvastatin and simvastatin reduced the basal secretion of IL-6 and the cell viability of the microglia, but only atorvastatin reduced LPS- and Abeta1-40-induced IL-6 secretion. Both statins potentiated the Abeta1-40-induced reduction in cell viability. The data indicate the importance of also considering the microglial responses to statins in evaluation of their effects in AD and other neurodegenerative disorders with an inflammatory component., ((c) 2005 Wiley-Liss, Inc.)

Statins reduce cholesterol levels through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis. The cholesterol-lowering effect of statins is also due to an increase in the uptake of cholesterol by cells as a result of intracellular cholesterol depletion and enhanced expression of low-density lipoprotein (LDL) receptors. The use of statins as lipid-lowering agents has lead to remarkable changes in the treatment and prevention of ischemic heart disease. Results of large clinical trials of patients with ischemic heart disease have demonstrated that statins reduce inflammatory markers such as C-reactive protein, an independent risk factor in the disease. Statins exhibit properties that are beyond their lipid-lowering effects. These non-lipid-lowering properties involve the inhibition of the isoprenoid pathway through decreased synthesis of many nonsteroidal isoprenoid compounds. The focus on the immunomodulatory effect of statins is the result of the positive outcome of pravastatin treatment in cardiac transplantation patients, as well as angiographic regression studies showing insignificant changes in the degree of coronary stenosis despite a large reduction in cardiac events. Statin treatment reduces the risk of ischemic stroke despite the fact that LDL cholesterol is not directly associated with the risk of stroke. This observation lead to the investigation of the role of statins in inflammation and the immune system. Recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma (IFN-gamma), leading to repression of MHC II-mediated T-cell activation. Furthermore, statins inhibit the expression of specific cell surface receptors on monocytes, adhesion molecules and also integrin-dependent leucocyte adhesion. While statins may stimulate the secretion of caspase-1, IL-1beta and IL-18 in peripheral mononuclear cells in response to Mycobacterium tuberculosis, they exhibit additional effects on inflammation by decreasing IL-6 synthesis in human vascular smooth muscle cells (VSMC) in vitro. The focus of this monograph is to highlight the role of statins in the modulation of the immune system and inflammatory processes., (Copyright 2005 Prous Science. All rights reserved.)

3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, statins, are widely used cholesterol-lowering drugs and have been shown to have anticancer effects in many models. We have investigated the effect of statins on Mdm2, a p53-specific ubiquitin ligase. It was found that pravastatin induced Mdm2 phosphorylation at Ser166 and at 2A10 antibody-specific epitopes in HepG2 cells, while mRNA levels were unchanged. Furthermore, pravastatin was found to induce phosphorylation of mTOR at Ser2448. Ser166 phosphorylation of Mdm2 was abrogated by an inhibitor of mTOR, rapamycin, but not by the PI3-kinase inhibitors LY294002 and wortmannin. Ser166 phosphorylation of Mdm2 has been associated to active Mdm2 and has been shown to increase its ubiquitin ligase activity and lead to increased p53 degradation. Our data show that statins attenuated the p53 response to DNA damage. Thus, in HepG2 cells pravastatin and simvastatin pretreatment attenuated the p53 response to DNA damage induced by 5-fluorouracil and benzo(a)pyrene. Similar attenuation was induced when p53 stabilization was induced by the inhibitor of nuclear export, leptomycin B. Furthermore, in the DNA-damaged cells, half-lives of Mdm2 and p53 were decreased by statins, indicating a more rapid formation of p53/Mdm2 complexes and facilitated p53 degradation. The induction of p53 responsive genes and apoptosis was attenuated. Mdm2 and p53 were also studied in vivo in rat liver employing immunohistochemistry, and it was found that constitutive Mdm2 expression was changed in livers of pravastatin-treated rats. We also show that the p53 response to a challenging dose of diethylnitrosamine was attenuated in hepatocytes in situ and in primary cultures of hepatocytes by pravastatin pretreatment. Taken together, these data indicate that statins induce an mTOR-dependent Ser166 phosphorylation of Mdm2, and this effect may attenuate the duration and intensity of the p53 response to DNA damage in hepatocytes.

An increasing number of studies suggest that disturbances in cholesterol homeostasis may promote the formation and deposition of beta-amyloid (A beta) and the progression of Alzheimer's disease (AD). In this paper, we have analyzed the effect of the lipid-lowering compound rosuvastatin on apoptosis and caspase-3 activity in human neuroblastoma SH-SY5Y cells. Exposure of SH-SY5Y cells to A beta(1-42) alone resulted in a significantly increased caspase-3 activity approximately by 35% (135+/-15%, p<0.05), and decreased alpha-secretase activity by 34% (67.4+/-2.7%, p<0.001) compared to the controls (100+/-18.1%). Rosuvastatin alone decreased caspase-3 activity by 15% (85.3+/-1.5%, p<0.0005) compared to the controls and by 50% to cells exposed to A beta alone (p<0.00005). Cells exposed to rosuvastatin alone had a higher alpha-secretase activity compared to cells exposed to A beta (76.4+/-23.8%, n.s.) but a slightly lower activity compared to the controls (n.s.). Pre-treatment of SY-SY5Y cells with rosuvastatin prior to incubation with A beta(1-42) resulted in decreased caspase-3 activity by approximately 15% compared to the controls and by approximately 48% (86.8+/-16.9%, p<0.05) compared to cells treated with A beta(1-42) alone. Also, alpha-secretase activity was increased by approximately 50% compared to the controls and by 84% (151.3+/-10.1%, p<0.05), compared to cells treated with A beta(1-42) alone. Mevalonate abrogated the effect of rosuvastatin in vitro. To our knowledge, this is the first study demonstrating that the hydrophilic compound rosuvastatin decreases caspase-3 activity and increases alpha-secretase activity in human neuroblastoma SH-SY5Y cells exposed to A beta in vitro. These effects are essential for modulation of the amyloidogenic pathway and mediators of apoptosis in AD.

Hypercholesterolemia has been suggested as a risk factor for Alzheimer's disease (AD). A genetic risk factor for AD is the E4 allele of apolipoprotein E (apoE). ApoE is the major lipoprotein transporter in the brain, and is mainly produced by glial cells. The present study is focussed on analysing the effects of high cholesterol (HC) diet, duration 9 months, on glial activation in the brain, both in wild type (WT) mice and in mice with a null mutation in the apoE gene (knock-out, KO) mice. The activation of astrocytes and microglia was analysed after immunohistochemical labelling of glial fibrillary acidic protein (GFAP), and F4/80, respectively. In addition, the expression of the antioxidant enzyme NAD(P)H:quinone oxidoreductase (NQO1) was analysed. There was a marked stimulation of astrocyte and microglial activation as well as induced expression of NQO1 in the hippocampus and cerebral cortex upon HC diet. Furthermore, there was significant astrocyte activation in the apoE KO mice, as compared to the WT mice, on ND. The long time exposure to HC diet combined with apoE deficiency resulted in a synergistic effect on the expression of NQO1 in the brain.

Statins are known to exert a number of biological effects apart from reducing cholesterol synthesis. The results of recent studies indicate that patients treated with pravastatin have a lower prevalence of diagnosed Alzheimer's disease (AD). These observations prompted us to examine the effects of pravastatin on Alzheimer's peptide (Abeta(1-42))-induced pro-inflammatory activation in the human glioma cell line in vitro. Cells alone or cells pre-treated with pravastatin (0.1mg x ml(-1)) for 24h were stimulated with 5 microM of freshly dissolved Abeta(1-42) for the next 24h. The pre-treatment of cells with pravastatin diminished the capacity of Abeta to induce metalloproteinases, cytokine IL-6 and free radical levels. Although both pravastatin and Abeta(1-42) separately increased PPARgamma activity, the combination of Abeta(1-42) and pravastatin resulted in no effect on PPARgamma expression. These data indicate that soluble forms of Abeta(1-42), which are a potent stimulus of pro-inflammatory activation of glioma cells in vitro, could be a good target for pravastatin.

Statins reduce cholesterol levels through competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the key enzyme that regulates cholesterol synthesis. The cholesterol-lowering effect of statins is also due to an increase in the uptake of cholesterol by cells as a result of intracellular cholesterol depletion and enhanced expression of low-density lipoprotein (LDL) receptors. The use of statins as lipid-lowering agents has lead to remarkable changes in the treatment and prevention of ischemic heart disease. Results of large clinical trials of patients with ischemic heart disease have demonstrated that statins reduce inflammatory markers such as C-reactive protein, an independent risk factor in the disease. Statins exhibit properties that are beyond their lipid-lowering effects. These non-lipid-lowering properties involve the inhibition of the isoprenoid pathway through decreased synthesis of many nonsteroidal isoprenoid compounds. The focus on the immunomodulatory effect of statins is the result of the positive outcome of pravastatin treatment in cardiac transplantation patients, as well as angiographic regression studies showing insignificant changes in the degree of coronary stenosis despite a large reduction in cardiac events. Statin treatment reduces the risk of ischemic stroke despite the fact that LDL cholesterol is not directly associated with the risk of stroke. This observation lead to the investigation of the role of statins in inflammation and the immune system. Recent research data demonstrated that statins inhibit the induction of the major histocompatibility (MHC) class II expression by interferon-gamma (IFN-gamma), leading to repression of MHC II-mediated T-cell activation. Furthermore, statins inhibit the expression of specific cell surface receptors on monocytes, adhesion molecules and also integrin-dependent leucocyte adhesion. While statins may stimulate the secretion of caspase-1, IL-1beta and IL-18 in peripheral mononuclear cells in response to Mycobacterium tuberculosis, they exhibit additional effects on inflammation by decreasing IL-6 synthesis in human vascular smooth muscle cells (VSMC) in vitro. The focus of this monograph is to highlight the role of statins in the modulation of the immune system and inflammatory processes., (Copyright 2003 Prous Science. All rights reserved.)

Vascular risk factors such as hypertension and hypercholesterolemia during midlife increase the risk for Alzheimer's disease (AD). Treatment of hypercholesterolemia and other vascular risk factors may have great implications in the prevention of AD. Recent findings illustrate that the sterol metabolism in the brain is an active process, well controlled and regulated by 24-hydroxylase, an enzyme that is uniquely expressed in the brain. The use of statins in ischemic heart disease (IHD) has proven to be a phenomenal advance in pharmacological disease prevention and treatment. A growing body of evidence, suggest that statins exhibit additional benefits that are independent of their cholesterol-lowering actions. Statin treatment has also considerable effect in prevention of ischemic stroke. In animal models of ischemic stroke, statins have proven to reduce infarct size through up-regulation of endothelial nitric oxide synthases. Data from recent observational studies have revealed a potential role for statins in prevention of AD. The following review comments the processes leading to dementia including the involvement of cholesterol regulation, cerebral circulation and inflammation in development of dementia. The mechanisms by which statins may be beneficial in controlling these processes is discussed.

Statins are inhibitors of the rate-limiting step of cellular cholesterol synthesis. In vitro and in vivo studies suggest that statins have anti-inflammatory properties independent of their cholesterol-lowering effects. These observations prompted us to examine the effects of pravastatin (50 microM) and native or oxidized low density lipoprotein (nLDL or oxLDL) (50 microg ml(-1)) on primary human monocytes. We found that cells treated with pravastatin prior to nLDL and cells pre-treated with oxLDL prior to pravastatin showed increased activity of peroxisome proliferator-activated receptor gamma (PPAR gamma). Treatment of cells with drug either before incubation with oxLDL or afterwards suppressed nuclear factor kappa B (NF kappa B) expression and reduced uptake of(125)I-oxLDL by 1.7- and 1.5-fold, respectively. Pravastatin also increased PPAR gamma levels and abolished NF kappa B activity in non-stimulated monocytes. Statin added to monocytes prior to or after treatment with nLDL or oxLDL significantly inhibited generation of matrix metalloproteinases (MMPs), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor alpha (TNF- alpha). These data corroborate previous findings of the pleiotropic role of statins and also suggest the involvement of transcription factors such as PPAR gamma and NF kappa B in the modulation of the inflammatory processes by statins., (Copyright 2002 Elsevier Science Ltd.)

Epidemiological studies indicate that the risk of first ever stroke is strongly related to age. Based on the NASCET and ECST results, carotid endarterectomy (CEA) is a well-established indication for the prevention of ischemic stroke in patients with 70-99% symptomatic internal carotid artery (ICA) stenosis and in selective cases with moderate stenosis (50-69%). A recent analysis of data from the NASCET group, clearly demonstrates that elderly patients (age > 75 years) with symptomatic ICA stenosis benefit more from CEA compared to younger patients. However, the NASCET collaborators point out that the greater benefits achieved in patients older than 75 years compared to other age groups in the trial depends on the fact that CEA was performed on the elderly having a higher risk of ipsilateral ischemic stroke if treated medically and the lowest surgical risk. In order to obtain the treatment benefit reported, operation performed by skilled surgeons and meticulous medical screening of the elderly patients is recommended to exclude life-threatening conditions.