Safety and efficacy of tenecteplase in patients with wake-up stroke assessed by non-contrast CT (TWIST): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Current evidence supports the use of intravenous thrombolysis with alteplase in patients with wake-up stroke selected with MRI or perfusion imaging and is recommended in clinical guidelines. However, access to advanced imaging techniques is often scarce. We aimed to determine whether thrombolytic treatment with intravenous tenecteplase given within 4·5 h of awakening improves functional outcome in patients with ischaemic wake-up stroke selected using non-contrast CT. METHODS: TWIST was an investigator-initiated, multicentre, open-label, randomised controlled trial with blinded endpoint assessment, conducted at 77 hospitals in ten countries. We included patients aged 18 years or older with acute ischaemic stroke symptoms upon awakening, limb weakness, a National Institutes of Health Stroke Scale (NIHSS) score of 3 or higher or aphasia, a non-contrast CT examination of the head, and the ability to receive tenecteplase within 4·5 h of awakening. Patients were randomly assigned (1:1) to either a single intravenous bolus of tenecteplase 0·25 mg per kg of bodyweight (maximum 25 mg) or control (no thrombolysis) using a central, web-based, computer-generated randomisation schedule. Trained research personnel, who conducted telephone interviews at 90 days (follow-up), were masked to treatment allocation. Clinical assessments were performed on day 1 (at baseline) and day 7 of hospital admission (or at discharge, whichever occurred first). The primary outcome was functional outcome assessed by the modified Rankin Scale (mRS) at 90 days and analysed using ordinal logistic regression in the intention-to-treat population. This trial is registered with EudraCT (2014-000096-80), ClinicalTrials.gov (NCT03181360), and ISRCTN (10601890). FINDINGS: From June 12, 2017, to Sept 30, 2021, 578 of the required 600 patients were enrolled (288 randomly assigned to the tenecteplase group and 290 to the control group [intention-to-treat population]). The median age of participants was 73·7 years (IQR 65·9-81·1). 332 (57%) of 578 participants were male and 246 (43%) were female. Treatment with tenecteplase was not associated with better functional outcome, according to mRS score at 90 days (adjusted OR 1·18, 95% CI 0·88-1·58; p=0·27). Mortality at 90 days did not significantly differ between treatment groups (28 [10%] patients in the tenecteplase group and 23 [8%] in the control group; adjusted HR 1·29, 95% CI 0·74-2·26; p=0·37). Symptomatic intracranial haemorrhage occurred in six (2%) patients in the tenecteplase group versus three (1%) in the control group (adjusted OR 2·17, 95% CI 0·53-8·87; p=0·28), whereas any intracranial haemorrhage occurred in 33 (11%) versus 30 (10%) patients (adjusted OR 1·14, 0·67-1·94; p=0·64). INTERPRETATION: In patients with wake-up stroke selected with non-contrast CT, treatment with tenecteplase was not associated with better functional outcome at 90 days. The number of symptomatic haemorrhages and any intracranial haemorrhages in both treatment groups was similar to findings from previous trials of wake-up stroke patients selected using advanced imaging. Current evidence does not support treatment with tenecteplase in patients selected with non-contrast CT. FUNDING: Norwegian Clinical Research Therapy in the Specialist Health Services Programme, the Swiss Heart Foundation, the British Heart Foundation, and the Norwegian National Association for Public Health.

Long-Term Survival, Causes of Death, and Trends in 5-Year Mortality After Intracerebral Hemorrhage: The Tromsø Study.

BACKGROUND AND PURPOSE: Data on long-term survival after intracerebral hemorrhage (ICH) are scarce. In a population-based nested case-control study, we compared long-term survival and causes of death within 5 years in 30-day survivors of first-ever ICH and controls, assessed the impact of cardiovascular risk factors on 5-year mortality, and analyzed time trend in 5-year mortality in ICH patients over 2 decades. METHODS: We included 219 participants from the population-based Tromsø Study, who after the baseline participation had a first-ever ICH between 1994 to 2013 and 1095 age- and sex-matched participants without ICH. Cumulative survival was presented using the Kaplan-Meier method. Hazard ratios (HRs) for mortality and for the association between cardiovascular risk factors and 5-year mortality in 30-day survivors were estimated by stratified Cox proportional hazards models. Trend in 5-year mortality was assessed by logistic regression. RESULTS: Risk of death during follow-up (median time, 4.8 years) was increased in the ICH group compared with controls (HR, 1.62 [95% CI, 1.27-2.06]). Cardiovascular disease was the leading cause of death, with a higher proportion in ICH patients (22.9% versus 9.0%; P<0.001). Smoking increased the risk of 5-year mortality in cases and controls (HR, 1.59 [95% CI, 1.15-2.19]), whereas serum cholesterol was associated with 5-year mortality in cases only (HR, 1.39 [95% CI, 1.04-1.86]). Use of anticoagulants at ICH onset increased the risk of death (HR, 2.09 [95% CI, 1.09-4.00]). There was no difference according to ICH location (HR, 1.15 [95% CI, 0.56-2.37]). Five-year mortality did not change during the study period (odds ratio per calendar year, 1.01 [95% CI, 0.93-1.09]). CONCLUSIONS: Survival rates were significantly lower in cases than in controls, driven by a 2-fold increased risk of cardiovascular death. Smoking, serum cholesterol, and use of anticoagulant drugs were associated with increased risk of death in ICH patients. Five-year mortality rates in ICH patients remained stable over time.

Evaluation of Error Production in Animal Fluency and Its Relationship to Frontal Tracts in Normal Aging and Mild Alzheimer's Disease: A Combined LDA and Time-Course Analysis Investigation.

Semantic verbal fluency (VF), assessed by animal category, is a task widely used for early detection of dementia. A feature not regularly assessed is the occurrence of errors such as perseverations and intrusions. So far, no investigation has analyzed the how and when of error occurrence during semantic VF in aging populations, together with their possible neural correlates. The present study aims to address the issue using a combined methodology based on latent Dirichlet allocation (LDA) analysis for word classification together with a time-course analysis identifying exact time of errors' occurrence. LDA is a modeling technique that discloses hidden semantic structures based on a given corpus of documents. We evaluated a sample of 66 participants divided into a healthy young group (n = 24), healthy older adult group (n = 23), and group of patients with mild Alzheimer's disease (AD) (n = 19). We performed DTI analyses to evaluate the white matter integrity of three frontal tracts purportedly underlying error commission: anterior thalamic radiation, frontal aslant tract, and uncinate fasciculus. Contrasts of DTI metrics were performed on the older groups who were further classified into high-error rate and low-error rate subgroups. Results demonstrated a unique deployment of error commission in the patient group characterized by high incidence of intrusions in the first 15 s and higher rate of perseverations toward the end of the trial. Healthy groups predominantly showed very low incidence of perseverations. The DTI analyses revealed that the patients with AD committing high-error rate presented significantly more degenerated frontal tracts in the left hemisphere. Thus, our findings demonstrated that the appearance of intrusions, together with left hemisphere degeneration of frontal tracts, is a pathognomic trait of mild AD. Furthermore, our data suggest that the error commission of patients with AD arises from executive and working memory impairments related partly to deteriorated left frontal tracts.

Amyloid Plaques and Symptoms of Depression Links to Medical Help-Seeking due to Subjective Cognitive Decline.

BACKGROUND: Subjective cognitive decline (SCD) is associated with an increased risk of Alzheimer's disease (AD). However, patients reporting SCD to their general practitioner are not always referred to a memory clinic. OBJECTIVE: To investigate whether prior history of medical help-seeking is associated with AD biomarker abnormality, worse cognitive performance, and/or depressive symptoms in SCD. METHODS: We compared levels of cerebrospinal fluid (CSF) Aß1 - 42, cognitive performance, and depressive symptoms (15-item Geriatric Depression Scale, GDS-15) between healthy controls (n = 88), SCD with a history of medical help seeking (SCD-HS, n = 67), and SCD non help-seekers (SCD-NHS, n = 44). Cases with evidence of amyloid plaques (CSF Aß1 - 42 ≤708 ng/l) and symptoms of depression (GDS-15≥6) were determined in both SCD groups. RESULTS: The SCD-HS group had lower CSF Aß1 - 42 (p < 0.01), lower word list learning and memory recall (p < 0.0001), and an increased level of depressive symptoms (p < 0.0001) compared to controls and SCD-NHS cases. The SCD-HS group had more cases with symptoms of depression (n = 12, 18%) and amyloid plaques (n = 18, 27%) compared to SCD-NHS (n = 1, 2% and n = 7, 16%, respectively). None of the SCD-HS cases and only one SCD-NHS case had concurrent symptoms of depression and amyloid plaques. The SCD-HS cases showed equal word list learning and memory performance regardless of amyloid status or symptoms of depression. CONCLUSION: Medical help-seeking in SCD is associated with an increased risk of AD pathology or symptoms of depression. However, subtle memory deficits are seen in SCD help-seekers, also without amyloid plaques or symptoms of depression.

The association between anthropometric measures of adiposity and the progression of carotid atherosclerosis.

BACKGROUND: Few reports are available on the contribution of general and abdominal obesity to the progression of carotid atherosclerosis in late adulthood. This study investigated the impact of four simple anthropometric measures of general and abdominal obesity on the progression of carotid atherosclerosis and the extent to which the association between adiposity and the progression of plaque burden is mediated by cardiometabolic markers. METHODS: Four thousand three hundred forty-five adults (median age 60) from the population-based Tromsø Study were followed over 7 years from the first carotid ultrasound screening to the next. The progression of carotid atherosclerosis was measured in three ways: incidence of plaques in previously plaque-free participants; change in the number of plaques; and total plaque area (TPA). We used generalised linear models to investigate the association between each adiposity measure - body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) - and each outcome. Models were adjusted for potential confounders (age, sex, smoking, education, physical activity). The pathways through which any associations observed might operate were investigated by further adjusting for cardiometabolic mediators (systolic blood pressure, cholesterol, and HbA1c). RESULTS: There was little evidence that adiposity was related to the formation of new plaques during follow-up. However, abdominal adiposity was associated with TPA progression. WHtR showed the largest effect size (mean change in TPA per one standard deviation (SD) increase in WHtR of 0.665 mm2, 95% confidence interval 0.198, 1.133) while BMI showed the smallest. Effect sizes were substantially reduced after the adjustment for potential mediators. CONCLUSIONS: Abdominal obesity indirectly measured with WC seems more strongly associated with the progression of TPA than general obesity. These associations appear to be largely mediated by known cardiometabolic markers.

Progression of conventional cardiovascular risk factors and vascular disease risk in individuals: insights from the PROG-IMT consortium.

AIMS: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear. METHODS AND RESULTS: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events. CONCLUSION: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.

Demographically adjusted CERAD wordlist test norms in a Norwegian sample from 40 to 80 years.

Background/Objective: In recent years, several slightly younger cohorts have been established in order to study the preclinical and prodromal phases of dementia. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) wordlist memory test (WLT) is widely used in dementia research. However, culturally adapted and demographically adjusted test norms for younger ages are lacking.Method: This paper investigates effects of age, gender and years of education on test performance and offers demographically adjusted norms for the CERAD WLT using a regression-based norming procedure for the age span 40-80 years based on healthy controls (n = 227) from the Norwegian "Dementia Disease Initiation" (DDI) (n = 168) and "Trønderbrain" (n = 59) cohorts. In order to evaluate normative performance, we apply the norms to an independent sample of persons diagnosed with mild cognitive impairment (MCI = 168) and perform multiple regression analyses to evaluate adjustment of pertinent demographics.Results: CERAD WLT norms adjusted for effects of age, gender and educational level are proposed. The norms successfully adjusted for effects of age, gender and education in an independent sample of Norwegians with MCI.Conclusion: Demographically adjusted norms for the CERAD WLT for ages 40-80 years based on a Norwegian sample are proposed. To our knowledge, this is the first normative study of this test to offer demographically adjusted norms for this age span.

Dietary intake of marine n-3 polyunsaturated fatty acids and future risk of venous thromboembolism.

BACKGROUND: Studies on the association between long-chained n-3 polyunsaturated fatty acids (n-3 PUFAs) and risk of venous thromboembolism (VTE) are conflicting, potentially due to challenges related to assessment of n-3 PUFA intake and changes in diet during follow-up. OBJECTIVES: To investigate whether dietary intake of marine n-3 PUFAs was associated with risk of incident VTE in a population-based cohort with repeated assessments of n-3 PUFA intake. METHODS: We recruited 21 970 participants (after excluding 7570 with incomplete data) from the fourth (1994-1995) and sixth (2007-2008) surveys of the Tromsø Study, and recorded incident VTEs up to 2016. Intake of n-3 PUFAs was computed from self-reported consumption of fat and lean fish, fish spread, and supplements. Cox proportional hazards regression models with n-3 PUFA intake as a time-varying variable were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for VTE across quartiles (Q) of n-3 PUFA intake. RESULTS: There were 541 incident VTEs during follow-up. Compared to Q1, subjects in Q2-4 had 22%-26% lower risk of VTE (HR Q2 0.74, 95% CI 0.57-0.96; HR Q3 0.77, 95% CI 0.59-0.99; HR Q4 0.78, 95% CI 0.61-1.00). The association was most pronounced for provoked VTE, particularly provoked pulmonary embolism (PE), with risk estimates of 0.42 (95% CI 0.25-0.72), 0.40 (95% CI 0.23-0.68), and 0.61 (95% CI 0.38-0.96) for Q2-4, respectively. CONCLUSIONS: Dietary intake of marine n-3 PUFAs was associated with a lower risk of VTE, particularly provoked PE. The association displayed a threshold pattern and suggested a protective effect of an n-3 PUFA intake ≥4.7 g/week.

The impact of risk factor trends on intracerebral hemorrhage incidence over the last two decades-The Tromsø Study.

BACKGROUND: Studies on the relationship between temporal trends in risk factors and incidence rates of intracerebral hemorrhage are scarce. AIMS: To analyze temporal trends in risk factors and incidence rates of intracerebral hemorrhage using individual data from a population-based study. METHODS: We included 28,167 participants of the Tromsø Study enrolled between 1994 and 2008. First-ever intracerebral hemorrhages were registered through 31 December 2013. Hazard ratios (HRs) for intracerebral hemorrhage were analyzed by Cox proportional hazards models, risk factor levels over time by generalized estimating equations, and incidence rate ratios (IRR) by Poisson regression. RESULTS: We registered 219 intracerebral hemorrhages. Age, male sex, systolic blood pressure (BP), diastolic BP, and hypertension were associated with intracerebral hemorrhage. Hypertension was more strongly associated with non-lobar intracerebral hemorrhage (HR 5.08, 95% CI 2.86-9.01) than lobar intracerebral hemorrhage (HR 1.91, 95% CI 1.12-3.25). In women, incidence decreased significantly (IRR 0.46, 95% CI 0.23-0.90), driven by a decrease in non-lobar intracerebral hemorrhage. Incidence rates in men remained stable (IRR 1.27, 95% CI 0.69-2.31). BP levels were lower and decreased more steeply in women than in men. The majority with hypertension were untreated, and a high proportion of those treated did not reach treatment goals. CONCLUSIONS: We observed a significant decrease in intracerebral hemorrhage incidence in women, but not in men. A steeper BP decrease in women may have contributed to the diverging trends. The high proportion of untreated and sub-optimally treated hypertension calls for improved strategies for prevention of intracerebral hemorrhage.

Correction: Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration.

[This corrects the article DOI: 10.1371/journal.pone.0191172.].

Creatine kinase is associated with reduced inflammation in a general population: The Tromsø study.

BACKGROUND: Creatine kinase (CK) has been associated with reduced inflammation in obesity while inflammation is associated with obesity-related cardiovascular diseases. We investigated the relationship between CK and high sensitive C-reactive protein (hs-CRP) in a general population. METHODS: CK and hs-CRP were measured in the population-based Tromsø study that included entire birth cohorts and random samples of citizens between 30-87 years of age. The analyses were performed sex-stratified in 5969 men and 6827 women. RESULTS: CK correlated negatively with hs-CRP in men (r = -0.08, P <0.001) and women (r = -0.06, P <0.001). In univariable regression analyses, CK associated negatively with hs-CRP in men (ß = -0.14, 95% CI -0.19 to -0.10, P <0.001) and women (ß = -0.13, 95% CI -0.18 to -0.08, P <0.001). Mean CK declined from the 2. to the 4. quartiles of hs-CRP in both genders (P <0.001 for trends). There were positive correlations between CK and body mass index (BMI) in men (r = 0.10, P <0.001) and women (r = 0.07, P <0.001). Multiple regression analyses showed a 0.13 unit decrease in hs-CRP (mg/dl) per unit CK increase in men (95% CI -0.35 to -0.20) and 0.29 mg/dl in women (95% CI -0.36 to -0.21) when adjusted for age, BMI, lipids, s-glucose, s-creatinine, transaminases and coronary heart disease. CONCLUSION: CK were inversely and independently associated with hs-CRP in a general population. These data provide evidence that CK might have anti-inflammatory properties, but the mechanism and clinical implications are unclarified.

Fish consumption, fish oil supplements and risk of atherosclerosis in the Tromsø study.

BACKGROUND: Whether long-chain n-3 PUFAs of marine origin have an anti-atherogenic effect in the general population has hardly been studied. In this population-based study, we hypothesized that fatty fish and fish oil intake protect against development of novel atherosclerotic plaques and is associated with reduced plaque size. METHODS: We obtained questionnaire-based information on fish consumption and carotid ultrasonography from 3900 persons aged 45-74 years. The questionnaires were validated by measuring serum concentrations of PUFAs and triglycerides in a subgroup. At follow-up seven years later, 2983 (76%) went through a second ultrasound scanning. Logistic regression and general linear models were used to analyze the outcome (plaque presence and plaque area) as a function of fish consumption, including analyses stratified on fish oil supplements. RESULTS: At baseline, lean fish intake < 1 time/week vs. 1-1.9 times/week was associated with risk of plaque (OR 1.34, 95% CI 1.03-1.76). Fatty fish intake and use of fish oil supplements were not statistically significantly associated with atherosclerosis at baseline. In persons without plaque at baseline, total fish consumption ≥3 times/week vs. 1-1.9 times/week was associated with risk of novel plaque (OR 1.32, 95% CI 1.01-1.73) and larger plaque area (1.76 mm2 vs. 1.46 mm2, p = 0.02) at follow-up. Adjustments for use of fish oil supplements had no impact on the associations, and no interactions were seen between total, fatty or lean fish consumption and fish oil intake. CONCLUSIONS: We found no protective effect of fatty fish eating or fish oil supplements on atherosclerotic plaque formation or plaque area in a general population. Lean fish consumption was associated with a reduced risk for plaque in cross-sectional analysis, suggesting that the beneficial effects of fish consumption on atherosclerosis may be mediated through other mechanisms than n-3 PUFAs.

Joint Effect of Carotid Plaque and C-Reactive Protein on First-Ever Ischemic Stroke and Myocardial Infarction?

BACKGROUND: The joint effect of atherosclerosis and CRP (C-reactive protein) on risk of ischemic stroke (IS) and myocardial infarction (MI) has been sparsely studied. The aim of this study was to explore whether CRP mediates the risk of events in subjects with prevalent carotid plaque, examine synergism, and test whether CRP and carotid plaque add to risk prediction beyond traditional risk factors. METHODS AND RESULTS: CRP and carotid total plaque area (TPA) were measured in 10 109 participants in the Tromsø Study from 1994 to 2008. Incident IS (n=671) and MI (n=1079) were registered until December 31, 2013. We calculated hazard ratios (HRs) of MI and IS according to categories of CRP (<1, 1-3, and >3 mg/L) and plaque status (no plaque and TPA below and above median) in Cox proportional hazard models with time-varying covariates. Multivariable-adjusted CRP >3 versus <1 mg/L was associated with risk of IS (HR, 1.84; 95% confidence interval, 1.49-2.26) and MI (HR, 1.46; 95% confidence interval, 1.23-1.73). TPA above median versus no plaque was associated with risk for IS (HR, 1.65; 95% confidence interval, 1.36-2.01) and MI (HR, 1.64; 95% confidence interval, 1.41-1.92). In participants with plaque, adjustment for CRP minimally attenuated the risk estimates. The highest incidence rates for MI and IS were seen in the group with both CRP >3 mg/L and TPA is above the median. TPA and CRP combined added to risk prediction beyond traditional risk factors. CONCLUSIONS: The simultaneous presence of subclinical atherosclerosis and elevated CRP was associated with increased risk of IS and MI. The combined assessment of subclinical atherosclerosis and inflammatory biomarkers may improve cardiovascular disease risk stratification.

Predictive value for cardiovascular events of common carotid intima media thickness and its rate of change in individuals at high cardiovascular risk - Results from the PROG-IMT collaboration.

AIMS: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk. METHODS AND RESULTS: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C. CONCLUSIONS: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.

The contribution of obesity to carotid atherosclerotic plaque burden in a general population sample in Norway: The Tromsø Study.

BACKGROUND AND AIMS: Few studies have investigated the association of different measures of adiposity with carotid plaque. We aimed to investigate and compare the associations of four measures of adiposity: body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) with the presence of carotid plaque and total plaque area (TPA) in the right carotid artery. METHODS: We included 4906 individuals aged 31-88 years who participated in a population-based study with ultrasonography of the right carotid artery. Adiposity measures were converted to sex-specific SD units to allow comparison of effect sizes. TPA was log transformed due to its skewed distribution. Logistic and linear regression models were used respectively to investigate the association of each adiposity measure with the presence of plaque and with log-transformed TPA. Estimates were adjusted for potential confounders and mediators such as blood pressure and lipids. RESULTS: After adjustment for age, sex, smoking, and education level, there was strong evidence of an association between all adiposity measures and log-transformed TPA, whereas only WHR was weakly associated with presence of plaque. WHR showed the largest adjusted effect size for both log-transformed TPA (beta 0.055, 95%CI 0.028-0.081) and the presence of plaque (OR 1.07, 95%CI 1.01-1.15). Adjustment for mediators led to appreciable attenuation of observed effects. CONCLUSIONS: Adiposity is more consistently associated with extent of plaque burden than with whether an individual does or does not have any plaque. There was evidence that established biomarkers mediate much of this association. Abdominal adiposity appears to show the strongest effect.

Interleukin-6 is an independent predictor of progressive atherosclerosis in the carotid artery: The Tromsø Study.

BACKGROUND AND AIMS: Novel biomarkers are linked to cardiovascular disease (CVD). The aim of the present study was to investigate the association between 28 blood biomarkers and the formation and progression of carotid plaque. METHODS: In a nested case control study with 703 participants from the population based Tromsø Study, a large biomarker panel was measured in blood obtained at baseline. Carotid ultrasound was assessed both at baseline and at 6 years of follow-up. Four groups were defined: Group 1: no plaque at baseline or at follow-up (reference group); Group 2: novel plaque at follow-up; Group 3: stable plaque at follow-up; Group 4: progression of plaque at follow-up. By multinomial logistic regression analyses, we assessed the risk of being in the different plaque groups with regard to traditional cardiovascular risk factors and levels of biomarkers at baseline. RESULTS: Adjusted for traditional risk factors, interleukin-6 (IL-6) was an independent predictor of plaque progression (OR 1.44, 95% CI 1.12-1.85 per SD increase in IL-6 level). This result remained significant after inclusion of other novel biomarkers to the model, and when subjects with former CVD were excluded. Neopterin was protective of novel plaque formation (OR 0.73, 95% CI 0.57-0.93). Myeloperoxidase and Caspase-1 were independent predictors of plaque progression, but this effect disappeared when excluding subjects with former CVD. CONCLUSIONS: IL-6 is an independent predictor of plaque progression, suggesting that it may be a marker of progressive atherosclerosis in the general population and that its central role in CVD may be related to promotion of plaque growth.

Screening for Alzheimer's Disease: Cognitive Impairment in Self-Referred and Memory Clinic-Referred Patients.

BACKGROUND: Cognitive assessment is essential in tracking disease progression in AD. Presently, cohorts including preclinical at-risk participants are recruited by different means, which may bias cognitive and clinical features. We compared recruitment strategies to levels of cognitive functioning. OBJECTIVE: We investigate recruitment source biases in self-referred and memory clinic-referred patient cohorts to reveal potential differences in cognitive performance and demographics among at-risk participants. METHODS: We included 431 participants 40-80 years old. Participants were classified as controls (n = 132) or symptom group (n = 299). The symptom group comprised of subjective cognitive decline (SCD, n = 163) and mild cognitive impairment (MCI, n = 136). We compared cognitive performance and demographics in memory clinic-referrals (n = 86) to self-referred participants responding to advertisements and news bulletins (n = 179). Participants recruited by other means were excluded from analysis (n = 34). RESULTS: At symptom group level, we found significant reductions in cognitive performance in memory clinic-referrals compared to self-referrals. However, here reductions were only found within the MCI group. We found no differences in cognitive performance due to recruitment within the SCD group. The MCI group was significantly impaired compared to controls on all measures. Significant reductions in learning, and executive functions were also found for the SCD group. CONCLUSION: Regardless of recruitment method, both the SCD and MCI groups showed reductions in cognitive performance compared to controls. We found differences in cognitive impairment for memory clinic-referrals compared to self-referrals only within the MCI group, SCD-cases being equally affected irrespective of referral type.

Detecting At-Risk Alzheimer's Disease Cases.

While APOEɛ4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aß42 (pAß) and APOEɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAß and APOEɛ4 frequency compared to NC. Also, NCFD had higher APOEɛ4 frequencies without increased fraction of pAß compared to NC, and cases recruited from memory clinics had higher fractions of pAß and APOEɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAß enriched, whereas self-referred and NCFD cases more frequently are pAß negative but at risk (APOEɛ4 positive), suitable for primary intervention.

C-reactive protein in atherosclerosis - A risk marker but not a causal factor? A 13-year population-based longitudinal study: The Tromsø study.

BACKGROUND AND AIMS: CRP predicts cardiovascular disease (CVD) in large epidemiologic studies. The aim of the present study was to elucidate the role of CRP in atherosclerosis formation and progression in a prospective population-based study. METHODS: 6503 middle-aged subjects from The Tromsø study had serum CRP, carotid ultrasound and complete covariate data collected at baseline in 1994. Of these, 4730 and 2917 attended follow-up surveys with repeated assessments in 2001 and 2007, respectively. The cross-sectional associations between CRP and subclinical carotid atherosclerosis, and the longitudinal associations between baseline CRP and novel plaque formation and plaque progression were assessed in generalized estimating equations and linear mixed models stratified by sex. RESULTS: At baseline, traditional risk factors and plaque prevalence increased by CRP risk categories (<1 mg/L, 1-3 mg/L, and >3 mg/L) in both sexes. In cross-sectional analyses, multivariable-adjusted CRP was associated with plaque prevalence and total plaque area (TPA) in men and women. Age-adjusted baseline CRP >3 mg/L compared to CRP <1 mg/L predicted novel plaque formation (OR 1.44, CI 1.08-1.92) and TPA progression (ß = 0.0.029 (CI, 0.003-0.056)) in men, but not in women. In neither men nor women was baseline CRP a predictor of TPA-progression or novel plaque formation when adjusted for traditional risk factors. CONCLUSIONS: CRP was associated with plaque presence and TPA in cross-sectional analyses, but was not an independent predictor of novel plaque formation or plaque progression. Our findings suggest that CRP may link to CVD by other mechanisms than promoting formation and progression of atherosclerotic plaques.