Migraine or any headaches and white matter hyperintensities and their progression in women and men.

BACKGROUND: Cross-sectional and longitudinal studies have been conducted to investigate the association between migraine and any headache and white matter hyperintensities (WMH). However, studies are inconsistent regarding the strength of the association and its clinical significance. The aim of our study was to investigate the association between headache and its subtypes (migraine with aura (MigA+), migraine without aura (MigA-), non-migraine headache (nonMigHA)) and WMH and its course in the population-based 1000BRAINS study using state-of-the-art imaging techniques and migraine classification according to modified international classification of headache disorders. METHODS: Data from 1062 participants (45% women, 60.9 ± 13.0 years) with ever or never headache (neverHA) and complete quantitative (WMH volume) and qualitative (Fazekas classification) WMH data at first imaging and after 3.7 ± 0.7 years (393 participants) were analyzed. The sex-specific association between headache and its subtypes and WMH volume and its change was evaluated by linear regression, between headache and its subtypes and Fazekas score high vs. low (2-3 vs. 0-1) by log-binomial regression, adjusted for confounders. RESULTS: The lifetime prevalence of headache was 77.5% (10.5% MigA+, 26.9% MigA-, 40.1% nonMigHA). The median WMH volume was 4005 (IQR: 2454-6880) mm3 in women and 4812 (2842-8445) mm3 in men. Women with any headaches (all headache types combined) had a 1.23 [1.04; 1.45]-fold higher WMH volume than women who reported never having had a headache. There was no indication of higher Fazekas grading or more WMH progression in women with migraine or any headaches. Men with migraine or any headaches did not have more WMH or WMH progression compared to men without migraine or men who never had headache. CONCLUSIONS: Our study demonstrated no increased occurrence or progression of WMH in participants with mgiraine. But, our results provide some evidence of greater WMH volume in women with headache of any type including migraine. The underlying pathomechanisms and the reasons why this was not shown in men are unclear and require further research.

Epidemiology and Prognostic Implications of Coronary Artery Calcium in Asymptomatic Individuals With Prediabetes: A Multicohort Study.

OBJECTIVE: To describe the epidemiology and prognostic value of coronary artery calcium (CAC) in individuals with prediabetes. RESEARCH DESIGN AND METHODS: We pooled participants free of clinical atherosclerotic cardiovascular disease (ASCVD) from four prospective cohorts: the Multi-Ethnic Study of Atherosclerosis, Heinz Nixdorf Recall Study, Framingham Heart Study, and Jackson Heart Study. Two definitions were used for prediabetes: inclusive (fasting plasma glucose [FPG] ≥100 to <126 mg/dL and hemoglobin A1c [HbA1c] ≥5.7% to <6.5%, if available, and no glucose-lowering medications) and restrictive (FPG ≥110 to <126 mg/dL and HbA1c ≥5.7% to <6.5%, if available, among participants not taking glucose-lowering medications). RESULTS: The study included 13,376 participants (mean age 58 years; 54% women; 57% White; 27% Black). The proportions with CAC ≥100 were 17%, 22%, and 37% in those with euglycemia, prediabetes, and diabetes, respectively. Over a median (25th-75th percentile) follow-up time of 14.6 (interquartile range 7.8-16.4) years, individuals with prediabetes and CAC ≥100 had a higher unadjusted 10-year incidence of ASCVD (13.4%) than the overall group of those with diabetes (10.6%). In adjusted analyses, using the inclusive definition of prediabetes, compared with euglycemia, the hazard ratios (HRs) for ASCVD were 0.79 (95% CI 0.62, 1.01) for prediabetes and CAC 0, 0.70 (0.54, 0.89) for prediabetes and CAC 1-99, 1.54 (1.27, 1.88) for prediabetes and CAC ≥100, and 1.64 (1.39, 1.93) for diabetes. Using the restrictive definition, the HR for ASCVD was 1.63 (1.29, 2.06) for prediabetes and CAC ≥100. CONCLUSIONS: CAC ≥100 is frequent among individuals with prediabetes and identifies a high ASCVD risk subgroup in which the adjusted ASCVD risk is similar to that in individuals with diabetes.

Aggregation of type-2 diabetes, prediabetes, and metabolic syndrome in German couples.

We aimed to examine the concordance of type-2 diabetes, prediabetes and the metabolic syndrome in couples. In cross-sectional analyses, we used data from 1173 couples with index persons from the Heinz Nixdorf Recall Study (2011-2015), a population-based cohort study in Western Germany, and partners from the associated Heinz Nixdorf Multigeneration Study (2013-2016). Mean age (standard deviation) was 67.2 (6.6) years in index persons, and 67.8 (7.7) years in partners. The exposure was the presence of diabetes, prediabetes or metabolic syndrome in index persons, the outcome was the presence of the same health status in partners. Diabetes was defined by either self-reported diagnosis, intake of antidiabetic drugs or insulin, or HbA1c ≥ 6.5%. If the index person had prediabetes or diabetes, the partner was 1.46 (95% CI 1.07-2.00) times more likely to have diabetes than partners of index persons without the condition in the crude model (adjusted model: 1.33 (0.97-1.83)). For self-reported diabetes and for the metabolic syndrome, the corresponding prevalence ratios were 1.33 (0.90-1.97) and 1.17 (1.03-1.32), respectively (adjusted models: 1.23 (0.77-1.94), 1.04 (0.91-1.18)). In German couples, there was weak to moderate concordance of type-2 diabetes, prediabetes and the metabolic syndrome in crude, but poor concordance in adjusted models.

Synergism between coexisting eye diseases and sex in increasing the prevalence of the dry eye syndrome.

The aim was to investigate prevalence of dry eye syndrome (DES) in a population-based sample in Germany. The association between coexisting eye diseases and DES was also of interest. We recontacted participants of the Heinz Nixdorf Recall study between 2018 and 2021 by postal questionnaire that included the Women's Health Study questionnaire on DES. We estimated prevalence of DES and examined DES-associated factors among 2095 participants aged 62-91 years. We performed interaction analyses between sex and coexisting eye diseases in relation to the DES prevalence and performed bias analyses to examine the robustness of the results. The DES prevalence was 31.5% (34-36% after correction for potential non-response bias, 24.1% after correction for outcome misclassification) and it was almost 2.1-times higher in women than in men (women 42.3%, men 20.4%). Among DES subjects, 70.3% had received treatment in the previous 12 months. There was synergism between female sex and coexisting eye diseases (cataract, glaucoma, macular degeneration) in terms of DES prevalence. The extrapolated numbers of patients aged 62-91 years with DES in Germany are 1.1-1.3 million men and 6.1-6.8 million women. The observed synergism may be explained by differences in ocular physiology, subjective perception and response behavior. Women with eye diseases (cataract, glaucoma, macula degeneration) appear to have a markedly higher susceptibility to suffer from DES than men, so that a diagnostic workup of DES symptoms is particularly justified in women with these eye diseases.

Current use of percutaneous image-guided tumor ablation for the therapy of liver tumors: lessons learned from the registry of the German Society for Interventional Radiology and Minimally Invasive Therapy (DeGIR) 2018-2022.

OBJECTIVES: Percutaneous image-guided tumor ablation of liver malignancies has become an indispensable therapeutic procedure. The aim of this evaluation of the prospectively managed multinational registry of the voluntary German Society for Interventional Radiology and Minimally Invasive Therapy (DeGIR) was to analyze its use, technical success, and complications in clinical practice. MATERIALS AND METHODS: All liver tumor ablations from 2018 to 2022 were included. Technical success was defined as complete ablation of the tumor with an ablative margin. RESULTS: A total of 7228 liver tumor ablations from 136 centers in Germany and Austria were analyzed. In total, 31.4% (2268/7228) of patients were female. Median age was 67 years (IQR 58-74 years). Microwave ablation (MWA) was performed in 65.1% (4703/7228), and radiofrequency ablation (RFA) in 32.7% (2361/7228). Of 5229 cases with reported tumor etiology, 60.3% (3152/5229) of ablations were performed for liver metastases and 37.3% (1950/5229) for hepatocellular carcinoma. The median lesion diameter was 19 mm (IQR 12-27 mm). In total, 91.8% (6636/7228) of ablations were technically successful. The rate of technically successful ablations was significantly higher in MWA (93.9%, 4417/4703) than in RFA (87.3%, 2061/2361) (p < 0.0001). The total complication rate was 3.0% (214/7228) and was significantly higher in MWA (4.0%, 189/4703) than in RFA (0.9%, 21/2361, p < 0.0001). Additional needle track ablation did not increase the rate of major complications significantly (24.8% (33/133) vs. 28.4% (23/81), p = 0.56)). CONCLUSION: MWA is the most frequent ablation method. Percutaneous image-guided liver tumor ablations have a high technical success rate, which is higher for MWA than RFA. The complication rate is generally low but is higher for MWA than RFA. CLINICAL RELEVANCE STATEMENT: Percutaneous image-guided liver ablation using microwave ablation and radiofrequency ablation are effective therapeutic procedures with low complication rates for the treatment of primary and secondary liver malignancies. KEY POINTS: • Percutaneous image-guided liver tumor ablations have a high technical success rate, which is higher for microwave ablation than radiofrequency ablation. • Microwave ablation is the most frequent ablation method ahead of radiofrequency ablation. • The complication rate is generally low but is higher for microwave ablation than radiofrequency ablation.

Identification of radiomic biomarkers in a set of four skeletal muscle groups on Dixon MRI of the NAKO MR study.

In this work, we propose a processing pipeline for the extraction and identification of meaningful radiomics biomarkers in skeletal muscle tissue as displayed using Dixon-weighted MRI. Diverse and robust radiomics features can be identified that may be of aid in the accurate quantification e.g. varying degrees of sarcopenia in respective muscles of large cohorts. As such, the approach comprises the texture feature extraction from raw data based on well established approaches, such as a nnU-Net neural network and the Pyradiomics toolbox, a subsequent selection according to adequate conditions for the muscle tissue of the general population, and an importance-based ranking to further narrow the amount of meaningful features with respect to auxiliary targets. The performance was investigated with respect to the included auxiliary targets, namely age, body mass index (BMI), and fat fraction (FF). Four skeletal muscles with different fiber architecture were included: the mm. glutaei, m. psoas, as well as the extensors and adductors of the thigh. The selection allowed for a reduction from 1015 available texture features to 65 for age, 53 for BMI, and 36 for FF from the available fat/water contrast images considering all muscles jointly. Further, the dependence of the importance rankings calculated for the auxiliary targets on validation sets (in a cross-validation scheme) was investigated by boxplots. In addition, significant differences between subgroups of respective auxiliary targets as well as between both sexes were shown to be present within the ten lowest ranked features by means of Kruskal-Wallis H-tests and Mann-Whitney U-tests. The prediction performance for the selected features and the ranking scheme were verified on validation sets by a random forest based multi-class classification, with strong area under the curve (AUC) values of the receiver operator characteristic (ROC) of 73.03 ± 0.70 % and 73.63 ± 0.70 % for the water and fat images in age, 80.68 ± 0.30 % and 88.03 ± 0.89 % in BMI, as well as 98.36 ± 0.03 % and 98.52 ± 0.09 % in FF.

Blood Kallikrein-8 and Non-Amnestic Mild Cognitive Impairment: An Exploratory Study.

Background: Blood kallikrein-8 is supposed to be a biomarker for mild cognitive impairment (MCI) due to Alzheimer's disease (AD), a precursor of AD dementia. Little is known about the association of kallikrein-8 and non-AD type dementias. Objective: To investigate whether blood kallikrein-8 is elevated in individuals with non-amnestic MCI (naMCI), which has a higher probability to progress to a non-AD type dementia, compared with cognitively unimpaired (CU) controls. Methods: We measured blood kallikrein-8 at ten-year follow-up (T2) in 75 cases and 75 controls matched for age and sex who were participants of the population-based Heinz Nixdorf Recall study (baseline: 2000-2003). Cognitive performance was assessed in a standardized manner at five (T1) and ten-year follow-up. Cases were CU or had subjective cognitive decline (SCD) at T1 and had naMCI at T2. Controls were CU at both follow-ups. The association between kallikrein-8 (per 500 pg/ml increase) and naMCI was estimated using conditional logistic regression: odds ratios (OR) and 95% confidence intervals (95% CI) were determined, adjusted for inter-assay variability and freezing duration. Results: Valid kallikrein-8 values were measured in 121 participants (45% cases, 54.5% women, 70.5±7.1 years). In cases, the mean kallikrein-8 was higher than in controls (922±797 pg/ml versus 884±782 pg/ml). Kallikrein-8 was not associated with having naMCI compared to being CU (adjusted; OR: 1.03 [95% CI: 0.80-1.32]). Conclusion: This is the first population-based study that shows that blood kallikrein-8 tends not to be elevated in individuals with naMCI compared with CU. This adds to the evidence of the possible AD specificity of kallikrein-8.

Association of regional white matter hyperintensities with hypertension and cognition in the population-based 1000BRAINS study.

BACKGROUND: White matter hyperintensities of presumed vascular origin (WMH) are frequent in cerebral magnetic resonance imaging of older people. They are promoted by vascular risk factors, especially hypertension, and are associated with cognitive deficits at the group level. It has been suggested that not only the severity, but also the location, of lesions might critically influence cognitive deficits and represent different pathologies. METHODS: In 560 participants (65.2 ± 7.5 years, 51.4% males) of the population-based 1000BRAINS study, we analyzed the association of regional WMH using Fazekas scoring separately for cerebral lobes, with hypertension and cognition. RESULTS: WMH most often affected the frontal lobe (83.7% score >0), followed by the parietal (75.8%), temporal (32.7%), and occipital lobe (7.3%). Higher Fazekas scores in the frontal, parietal, and temporal lobe were associated with higher blood pressure and antihypertensive treatment in unadjusted ordinal regression models and in models adjusted for age, sex, and vascular risk factors (e.g., age- and sex-adjusted odds ratio = 1.14, 95% confidence interval = 1.03-1.25 for the association of frontal lobe WMH Fazekas score with systolic blood pressure [SBP] [per 10 mm Hg]; 1.13 [1.02-1.23] for the association of parietal lobe score with SBP; 1.72 [1.19-2.48] for the association of temporal lobe score with antihypertensive medications). In linear regressions, higher frontal lobe scores were associated with lower performance in executive function and non-verbal memory, and higher parietal lobe scores were associated with lower performance in executive function, verbal-, and non-verbal memory. CONCLUSIONS: Hypertension promotes WMH in the frontal, parietal, and temporal lobe. WMH in the frontal and parietal lobe are associated with reduced executive function and memory.

Long-term air pollution exposure and Parkinson's disease mortality in a large pooled European cohort: An ELAPSE study.

BACKGROUND: The link between exposure to ambient air pollution and mortality from cardiorespiratory diseases is well established, while evidence on neurodegenerative disorders including Parkinson's Disease (PD) remains limited. OBJECTIVE: We examined the association between long-term exposure to ambient air pollution and PD mortality in seven European cohorts. METHODS: Within the project 'Effects of Low-Level Air Pollution: A Study in Europe' (ELAPSE), we pooled data from seven cohorts among six European countries. Annual mean residential concentrations of fine particulate matter (PM2.5), nitrogen dioxide (NO2), black carbon (BC), and ozone (O3), as well as 8 PM2.5 components (copper, iron, potassium, nickel, sulphur, silicon, vanadium, zinc), for 2010 were estimated using Europe-wide hybrid land use regression models. PD mortality was defined as underlying cause of death being either PD, secondary Parkinsonism, or dementia in PD. We applied Cox proportional hazard models to investigate the associations between air pollution and PD mortality, adjusting for potential confounders. RESULTS: Of 271,720 cohort participants, 381 died from PD during 19.7 years of follow-up. In single-pollutant analyses, we observed positive associations between PD mortality and PM2.5 (hazard ratio per 5 µg/m3: 1.25; 95% confidence interval: 1.01-1.55), NO2 (1.13; 0.95-1.34 per 10 µg/m3), and BC (1.12; 0.94-1.34 per 0.5 × 10-5m-1), and a negative association with O3 (0.74; 0.58-0.94 per 10 µg/m3). Associations of PM2.5, NO2, and BC with PD mortality were linear without apparent lower thresholds. In two-pollutant models, associations with PM2.5 remained robust when adjusted for NO2 (1.24; 0.95-1.62) or BC (1.28; 0.96-1.71), whereas associations with NO2 or BC attenuated to null. O3 associations remained negative, but no longer statistically significant in models with PM2.5. We detected suggestive positive associations with the potassium component of PM2.5. CONCLUSION: Long-term exposure to PM2.5, at levels well below current EU air pollution limit values, may contribute to PD mortality.

Diagnostic Cardiac CT for the Improvement of Cardiovascular Event Prediction.

BACKGROUND: The aim of the long-term Heinz Nixdorf Recall Study (observation period 20 years) was to establish the extent to which computed tomography (CT) improves the predictability of cardiovascular events relative to determination of risk factors alone. METHODS: In the period 2000-2003, study staff examined 4355 probands (53% of them female) aged 45-75 years with no signs of cardiovascular disease. The Atherosclerotic Cardiovascular Disease (ASCVD) score was calculated on the basis of demographic data and cardiovascular risk factors. Cardiac CT was carried out over the same period and coronary artery calcification (CAC) was graded according to the Agatston score. RESULTS: The median duration of follow-up was 18.2 years for men and 17.8 years for women. Myocardial infarction or stroke occurred in 458 (11%) of the 4154 participants with complete data. Overall, estimation of risk using a combination of ASCVD score and CAC grade was superior to the ASCVD score alone-even after 10 and 20 years. Classification into established risk categories improved by 12.2% (95% confidence interval: [5.3%; 18.1%]). In the highest ASCVD risk category, we observed occurrence of a cardiovascular event over 20 years for 14% [5.0%; 23.1%] of probands with a CAC score = 0 but for 34.2% [27.5%; 41.4%] of those with a CAC score ≥ 400. In the lowest ASCVD risk category, an event occurred in 2.4% [1.4%; 3.7%] of probands with a CAC score = 0 and in 23.5% [2.3%; 35.8%] of those with a CAC score ≥ 400. CONCLUSION: Even after 20 years, individual risk prediction is improved by addition of CT-based determination of coronary artery calcification to the ASCVD score. Therefore, assessment of ASCVD risk factors should be complemented more widely by cardiac CT in the primary prevention of cardiovascular disease.

Fluctuation of depressive symptoms in cognitively unimpaired participants and the risk of mild cognitive impairment 5 years later: Results of the Heinz Nixdorf Recall study.

Background: Depression might be an independent risk factor for cognitive decline, a prodromal dementia symptom or a reaction to cognitive/functional impairment. Objective: To investigate the association between (1) depressive symptoms and (2) depressive symptom patterns over 13 years with incident mild cognitive impairment (MCI) 5 years later. Materials and methods: We included 724/823 cognitively unimpaired men/women who participated in the population-based Heinz Nixdorf Recall study (t1: 2005-2008, ø62.9 years; t2: 2010-2015, ø68.1 years). Depressive symptoms were assessed in the study center and during six postal follow-ups using the short form of the Center for Epidemiologic Studies Depression Scale (CES-D). Relative risks (RR; 95% confidence intervals) for MCI at t2 (men/women: 71/76) were estimated for CES-D at t1 (linear and dichotomized at ≥17, cut-off for clinically relevant depressive symptoms) and CES-D fluctuations over 13 years (stable low, large fluctuations, stable high/stable around cut-off) using log-linear regression models with Poisson working likelihood adjusted for age, sex, education, diabetes mellitus, coronary heart disease, and stroke. Results: Fully adjusted risk for MCI at t2 (per CES-D point increase at t1) was elevated for the total cohort (1.053, 1.031-1.076), men (1.046, 1.012-1.081), and women (1.059, 1.029-1.090). Applying the dichotomized CES-D, risk for MCI was substantially increased for the total cohort [2.22 (1.38-3.58)] and in women [2.59 (1.46-4.58)]. Large CES-D fluctuations and stable high/stable around cut-off were associated with increased RR for MCI in the total cohort and in women compared to stable low symptoms. Conclusion: Depressive symptoms predicted MCI in cognitively unimpaired participants of our population-based study. Adequate treatment of depression may therefore contribute to the maintenance of normal cognition and delay dementia onset.

Long-term exposure to air pollution and mortality from dementia, psychiatric disorders, and suicide in a large pooled European cohort: ELAPSE study.

Ambient air pollution is an established risk factor for premature mortality from chronic cardiovascular, respiratory and metabolic diseases, while evidence on neurodegenerative diseases and psychiatric disorders remains limited. We examined the association between long-term exposure to air pollution and mortality from dementia, psychiatric disorders, and suicide in seven European cohorts. Within the multicenter project 'Effects of Low-Level Air Pollution: A Study in Europe' (ELAPSE), we pooled data from seven European cohorts from six countries. Based on the residential addresses, annual mean levels of fine particulate matter (PM2.5), nitrogen dioxide (NO2), black carbon (BC), ozone (O3), and 8 PM2.5 components were estimated using Europe-wide hybrid land-use regression models. We applied stratified Cox proportional hazard models to investigate the associations between air pollution and mortality from dementia, psychiatric disorders, and suicide. Of 271,720 participants, 900 died from dementia, 241 from psychiatric disorders, and 164 from suicide, during a mean follow-up of 19.7 years. In fully adjusted models, we observed positive associations of NO2 (hazard ratio [HR] = 1.38; 95 % confidence interval [CI]: 1.13, 1.70 per 10 µg/m3), PM2.5 (HR = 1.29; 95 % CI: 0.98, 1.71 per 5 µg/m3), and BC (HR = 1.37; 95 % CI: 1.11, 1.69 per 0.5 × 10-5/m) with psychiatric disorders mortality, as well as with suicide (NO2: HR = 1.13 [95 % CI: 0.92, 1.38]; PM2.5: HR = 1.19 [95 % CI: 0.76, 1.87]; BC: HR = 1.08 [95 % CI: 0.87, 1.35]), and no association with dementia mortality. We did not detect any positive associations of O3 and 8 PM2.5 components with any of the three mortality outcomes. Long-term exposure to NO2, PM2.5, and BC may lead to premature mortality from psychiatric disorders and suicide.

Association between Long-Term Air Pollution, Chronic Traffic Noise, and Resting-State Functional Connectivity in the 1000BRAINS Study.

BACKGROUND: Older adults show a high variability in cognitive performance that cannot be explained by aging alone. Although research has linked air pollution and noise to cognitive impairment and structural brain alterations, the potential impact of air pollution and noise on functional brain organization is unknown. OBJECTIVE: This study examined the associations between long-term air pollution and traffic noise with measures of functional brain organization in older adults. We hypothesize that exposures to high air pollution and noise levels are associated with age-like changes in functional brain organization, shown by less segregated brain networks. METHODS: Data from 574 participants (44.1% female, 56-85 years of age) in the German 1000BRAINS study (2011-2015) were analyzed. Exposure to particulate matter (PM10, PM2.5, and PM2.5 absorbance), accumulation mode particle number (PNAM), and nitrogen dioxide (NO2) was estimated applying land-use regression and chemistry transport models. Noise exposures were assessed as weighted 24-h (Lden) and nighttime (Lnight) means. Functional brain organization of seven established brain networks (visual, sensorimotor, dorsal and ventral attention, limbic, frontoparietal and default network) was assessed using resting-state functional brain imaging data. To assess functional brain organization, we determined the degree of segregation between networks by comparing the strength of functional connections within and between networks. We estimated associations between air pollution and noise exposure with network segregation, applying multiple linear regression models adjusted for age, sex, socioeconomic status, and lifestyle variables. RESULTS: Overall, small associations of high exposures with lesser segregated networks were visible. For the sensorimotor networks, we observed small associations between high air pollution and noise and lower network segregation, which had a similar effect size as a 1-y increase in age [e.g., in sensorimotor network, -0.006 (95% CI: -0.021, 0.009) per 0.3 ×10-5/m increase in PM2.5 absorbance and -0.004 (95% CI: -0.006, -0.002) per 1-y age increase]. CONCLUSION: High exposure to air pollution and noise was associated with less segregated functional brain networks. https://doi.org/10.1289/EHP9737.

Periventricular rather than deep white matter hyperintensities mediate effects of hypertension on cognitive performance in the population-based 1000BRAINS study.

OBJECTIVES: White matter hyperintensities (WMH) of presumed vascular origin are frequent in cerebral MRI of older people. They represent a sign of small vessel disease, are promoted by arterial hypertension, and relate to cognitive deficits. The interdependence of blood pressure and its treatment, WMH, and cognitive performance has not systematically been studied in population-based studies. METHODS: Consequently, we analysed the interdependence of SBP, DBP, and antihypertensive medications, as well as BP/treatment category, with WMH and cognitive performance in 560 participants of the population-based 1000BRAINS study. RESULTS: BP, its treatment, and BP/treatment category were moderately associated with cognitive performance (e.g. unadjusted ß â€Š= -0.10, 95%CI = -0.19 to -0.02 for the association of SBP (per standard deviation of 17.2 mmHg) with global cognition (per standard deviation of 0.5 z score)]. The harmful effect of BP on cognition was strongly mediated by periventricular hyperintensities (PVH), which were significantly associated with both SBP [ ß â€Š= 0.24, 95% CI = 0.14-0.34 (per 1-point-increase in Fazekas score)] and global cognition ( ß â€Š= -0.22, 95%CI =  -0.32 to -0.13). Thus, PVH mediated as much as 52% of the effects of SBP on cognitive performance. Mediation was less strong for deep white matter hyperintensities (DWMH, 16%), which showed less association with SBP ( ß â€Š= 0.14, 95% CI = 0.05-0.24) and global cognition ( ß â€Š= -0.12, 95%CI = -0.21 to -0.03). Regarding different cognitive domains, PVH most strongly mediated effects of SBP on nonverbal memory (94%) and executive function (81%). CONCLUSION: Our results indicate that PVH may predispose to cognitive impairment associated with hypertension, especially in the domains of nonverbal memory and executive function.

Coronary Artery Calcium Score to Refine the Use of PCSK9i in Asymptomatic Individuals: A Multicohort Study.

Background The value of coronary artery calcium (CAC) in the allocation of PCSK9i (proprotein convertase subtilisin/kexin type 9 inhibitors) among individuals without clinically evident atherosclerotic cardiovascular disease (ASCVD) is unknown for indications that do not require confirmed familial hypercholesterolemia. We aimed to assess the ability of CAC to stratify ASCVD risk under 3 non-familial hypercholesterolemia PCSK9i allocation paradigms. Methods and Results We included participants without clinically evident ASCVD from MESA (Multi-Ethnic Study of Atherosclerosis), CARDIA (Coronary Artery Risk Development in Young Adults) study, DHS (Dallas Heart Study), and HNR (Heinz Nixdorf Recall) study. Three PCSK9i eligibility scenarios were defined: a broad scenario informed only by high low-density lipoprotein cholesterol levels (N=567), a restrictive one combining higher low-density lipoprotein cholesterol levels and presence of ≥2 additional risk factors (N=127), and a high-risk scenario where individuals with subclinical organ damage or high estimated risk would be treated to achieve low-density lipoprotein cholesterol <55 mg/dL (N=471). The high-risk scenario had the highest ASCVD event rates (27.8% at 10 years). CAC=0 was observed in 35% participants in the broad scenario, 25% in the restrictive scenario, and 16% in the high-risk scenario. In all, CAC=0 was associated with the lowest incident ASCVD rates at 5 and 10 years, and CAC burden was independently associated with ASCVD events adjusting for traditional risk factors. Conclusions CAC may be used to refine the allocation of PCSK9i, potentially leading to a more conservative use if CAC=0. The value of CAC testing is greater in scenarios that use low-density lipoprotein cholesterol levels and/or traditional risk factors to define PCSK9i eligibility (CAC=0 present in 1 of 3-4 patients), whereas its prevalence is lower when allocation is informed by presence of noncoronary subclinical organ damage.

Long-Term Exposure to Source-Specific Fine Particles and Mortality─A Pooled Analysis of 14 European Cohorts within the ELAPSE Project.

We assessed mortality risks associated with source-specific fine particles (PM2.5) in a pooled European cohort of 323,782 participants. Cox proportional hazard models were applied to estimate mortality hazard ratios (HRs) for source-specific PM2.5 identified through a source apportionment analysis. Exposure to 2010 annual average concentrations of source-specific PM2.5 components was assessed at baseline residential addresses. The source apportionment resulted in the identification of five sources: traffic, residual oil combustion, soil, biomass and agriculture, and industry. In single-source analysis, all identified sources were significantly positively associated with increased natural mortality risks. In multisource analysis, associations with all sources attenuated but remained statistically significant with traffic, oil, and biomass and agriculture. The highest association per interquartile increase was observed for the traffic component (HR: 1.06; 95% CI: 1.04 and 1.08 per 2.86 µg/m3 increase) across five identified sources. On a 1 µg/m3 basis, the residual oil-related PM2.5 had the strongest association (HR: 1.13; 95% CI: 1.05 and 1.22), which was substantially higher than that for generic PM2.5 mass, suggesting that past estimates using the generic PM2.5 exposure response function have underestimated the potential clean air health benefits of reducing fossil-fuel combustion. Source-specific associations with cause-specific mortality were in general consistent with findings of natural mortality.

Exposure to surrounding greenness and natural-cause and cause-specific mortality in the ELAPSE pooled cohort.

BACKGROUND: The majority of studies have shown higher greenness exposure associated with reduced mortality risks, but few controlled for spatially correlated air pollution and traffic noise exposures. We aim to address this research gap in the ELAPSE pooled cohort. METHODS: Mean Normalized Difference Vegetation Index (NDVI) in a 300-m grid cell and 1-km radius were assigned to participants' baseline home addresses as a measure of surrounding greenness exposure. We used Cox proportional hazards models to estimate the association of NDVI exposure with natural-cause and cause-specific mortality, adjusting for a number of potential confounders including socioeconomic status and lifestyle factors at individual and area-levels. We further assessed the associations between greenness exposure and mortality after adjusting for fine particulate matter (PM2.5), nitrogen dioxide (NO2) and road traffic noise. RESULTS: The pooled study population comprised 327,388 individuals who experienced 47,179 natural-cause deaths during 6,374,370 person-years of follow-up. The mean NDVI in the pooled cohort was 0.33 (SD 0.1) and 0.34 (SD 0.1) in the 300-m grid and 1-km buffer. In the main fully adjusted model, 0.1 unit increment of NDVI inside 300-m grid was associated with 5% lower risk of natural-cause mortality (Hazard Ratio (HR) 0.95 (95% CI: 0.94, 0.96)). The associations attenuated after adjustment for air pollution [HR (95% CI): 0.97 (0.96, 0.98) adjusted for PM2.5; 0.98 (0.96, 0.99) adjusted for NO2]. Additional adjustment for traffic noise hardly affected the associations. Consistent results were observed for NDVI within 1-km buffer. After adjustment for air pollution, NDVI was inversely associated with diabetes, respiratory and lung cancer mortality, yet with wider 95% confidence intervals. No association with cardiovascular mortality was found. CONCLUSIONS: We found a significant inverse association between surrounding greenness and natural-cause mortality, which remained after adjusting for spatially correlated air pollution and traffic noise.

Long-term Air Pollution Exposure and Pneumonia-related Mortality in a Large Pooled European Cohort.

Rationale: Ambient air pollution exposure has been linked to mortality from chronic cardiorespiratory diseases, while evidence on respiratory infections remains more limited. Objectives: We examined the association between long-term exposure to air pollution and pneumonia-related mortality in adults in a pool of eight European cohorts. Methods: Within the multicenter project ELAPSE (Effects of Low-Level Air Pollution: A Study in Europe), we pooled data from eight cohorts among six European countries. Annual mean residential concentrations in 2010 for fine particulate matter, nitrogen dioxide (NO2), black carbon (BC), and ozone were estimated using Europe-wide hybrid land-use regression models. We applied stratified Cox proportional hazard models to investigate the associations between air pollution and pneumonia, influenza, and acute lower respiratory infections (ALRI) mortality. Measurements and Main Results: Of 325,367 participants, 712 died from pneumonia and influenza combined, 682 from pneumonia, and 695 from ALRI during a mean follow-up of 19.5 years. NO2 and BC were associated with 10-12% increases in pneumonia and influenza combined mortality, but 95% confidence intervals included unity (hazard ratios, 1.12 [0.99-1.26] per 10 µg/m3 for NO2; 1.10 [0.97-1.24] per 0.5 10-5m-1 for BC). Associations with pneumonia and ALRI mortality were almost identical. We detected effect modification suggesting stronger associations with NO2 or BC in overweight, employed, or currently smoking participants compared with normal weight, unemployed, or nonsmoking participants. Conclusions: Long-term exposure to combustion-related air pollutants NO2 and BC may be associated with mortality from lower respiratory infections, but larger studies are needed to estimate these associations more precisely.

Long-term exposure to low ambient air pollution concentrations and mortality among 28 million people: results from seven large European cohorts within the ELAPSE project.

BACKGROUND: Long-term exposure to ambient air pollution has been associated with premature mortality, but associations at concentrations lower than current annual limit values are uncertain. We analysed associations between low-level air pollution and mortality within the multicentre study Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE). METHODS: In this multicentre longitudinal study, we analysed seven population-based cohorts of adults (age ≥30 years) within ELAPSE, from Belgium, Denmark, England, the Netherlands, Norway, Rome (Italy), and Switzerland (enrolled in 2000-11; follow-up until 2011-17). Mortality registries were used to extract the underlying cause of death for deceased individuals. Annual average concentrations of fine particulate matter (PM2·5), nitrogen dioxide (NO2), black carbon, and tropospheric warm-season ozone (O3) from Europe-wide land use regression models at 100 m spatial resolution were assigned to baseline residential addresses. We applied cohort-specific Cox proportional hazard models with adjustment for area-level and individual-level covariates to evaluate associations with non-accidental mortality, as the main outcome, and with cardiovascular, non-malignant respiratory, and lung cancer mortality. Subset analyses of participants living at low pollutant concentrations (as per predefined values) and natural splines were used to investigate the concentration-response function. Cohort-specific effect estimates were pooled in a random-effects meta-analysis. FINDINGS: We analysed 28 153 138 participants contributing 257 859 621 person-years of observation, during which 3 593 741 deaths from non-accidental causes occurred. We found significant positive associations between non-accidental mortality and PM2·5, NO2, and black carbon, with a hazard ratio (HR) of 1·053 (95% CI 1·021-1·085) per 5 µg/m3 increment in PM2·5, 1·044 (1·019-1·069) per 10 µg/m3 NO2, and 1·039 (1·018-1·059) per 0·5 × 10-5/m black carbon. Associations with PM2·5, NO2, and black carbon were slightly weaker for cardiovascular mortality, similar for non-malignant respiratory mortality, and stronger for lung cancer mortality. Warm-season O3 was negatively associated with both non-accidental and cause-specific mortality. Associations were stronger at low concentrations: HRs for non-accidental mortality at concentrations lower than the WHO 2005 air quality guideline values for PM2·5 (10 µg/m3) and NO2 (40 µg/m3) were 1·078 (1·046-1·111) per 5 µg/m3 PM2·5 and 1·049 (1·024-1·075) per 10 µg/m3 NO2. Similarly, the association between black carbon and non-accidental mortality was highest at low concentrations, with a HR of 1·061 (1·032-1·092) for exposure lower than 1·5× 10-5/m, and 1·081 (0·966-1·210) for exposure lower than 1·0× 10-5/m. INTERPRETATION: Long-term exposure to concentrations of PM2·5 and NO2 lower than current annual limit values was associated with non-accidental, cardiovascular, non-malignant respiratory, and lung cancer mortality in seven large European cohorts. Continuing research on the effects of low concentrations of air pollutants is expected to further inform the process of setting air quality standards in Europe and other global regions. FUNDING: Health Effects Institute.