Characteristics of incidence hip fracture cases in older adults participating in the longitudinal AGES-Reykjavik study.

Poor physical function and body composition my partly predict the risk of falls leading to fracture regardless of bone mineral density. INTRODUCTION: To examine the relationship between body composition, physical function, and other markers of health with hip fractures in older community-dwelling Icelandic adults. METHODS: A prospective cohort of 4782 older adults from the AGES-Reykjavik study. Baseline recruitment took place between 2002 and 2006, and information on hip fractures occurring through 2012 was extracted from clinical records. Using multivariate regression analyses, baseline measures of bone health, physical function, and body composition were compared between those who later experienced hip fractures and to those who did not. Associations with the risk of fractures were quantified using Cox regression. RESULTS: Mean age was 76.3 years at baseline. After adjustment for age, regression showed that male hip fracture cases compared with non-cases had (mean (95% confidence interval)) significantly lower thigh muscle cross-sectional area - 5.6 cm2 (- 10.2, - 1.1), poorer leg strength - 28 N (- 49, - 7), and decreased physical function as measured by longer timed up and go test 1.1 s (0.5, 1.7). After adjustment for age, female cases had, compared with non-cases, lower body mass index - 1.5 kg/m2 (- 2.1, - 0.9), less lean mass - 1.6 kg (- 2.5, - 0.8), thigh muscle cross-sectional area - 4.4 cm2 (- 6.5, - 2.3), and worse leg strength - 16 N (- 25, - 6). These differences largely persisted after further adjustment for bone mineral density (BMD), suggesting that body composition may contribute to the risk of fracture independent of bone health. When examining the association between these same factors and hip fractures using Cox regression, the same conclusions were reached. CONCLUSIONS: After accounting for age and BMD, older adults who later experienced a hip fracture had poorer baseline measures of physical function and/or body composition, which may at least partly contribute to the risk of falls leading to fracture.

Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

Correction to: Characteristics of incidence hip fracture cases in older adults participating in the longitudinal AGES-Reykjavik study.

The original version of this article, published on 18 august 2020 contained a mistake. An author's name was misspelled.

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Marinesco bodies and substantia nigra neuron density in Parkinson's disease.

AIM: Marinesco bodies (MB) are intranuclear inclusions in pigmented neurons of the substantia nigra (SN). While rare in children, frequency increases with normal ageing and is high in Alzheimer's disease, dementia with Lewy bodies and other neurodegenerative disorders. Coinciding with the age-related rise in MB frequency is initiation of cell death among SN neurons. Whether MB have a role in this process is unknown. Our aim is to examine the association of MB with SN neuron density in Parkinson's disease (PD) in the Honolulu-Asia Aging Study. METHODS: Data on MB and neuron density were measured in SN transverse sections in 131 autopsied men aged 73-99 years at the time of death from 1992 to 2007. RESULTS: Marinesco body frequency was low in the presence vs. absence of PD (2.3% vs. 6.6%, P < 0.001). After PD onset, MB frequency declined as duration of PD increased (P = 0.006). Similar patterns were observed for SN neuron density. When MB frequency was low, neuron density was noticeably reduced in the SN ventrolateral quadrant, the region most vulnerable to PD neurodegeneration. Low MB frequency was unique to PD as its high frequency in non-PD cases was unrelated to parkinsonian signs and incidental Lewy bodies. Frequency was high in the presence of Alzheimer's disease and apolipoprotein ε4 alleles. CONCLUSIONS: While findings confirm that MB frequency is low in PD, declines in MB frequency continue with PD duration. The extent to which MB have a distinct relationship with PD warrants clarification. Further studies of MB could be important in understanding PD processes.

ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10(-6) were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10(-7) in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10(-9)). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.

Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility.

Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64,888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P=6.32 × 10(-5), odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells (P<0.005) and the prefrontal cortex (P<1.0 × 10(-6)). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.

Milk consumption throughout life and bone mineral content and density in elderly men and women.

UNLABELLED: Association between bone mineral density and bone mineral content in old age and milk consumption in adolescence, midlife, and old age was assessed. The association was strongest for milk consumption in midlife: those drinking milk daily or more often had higher bone mineral density and content in old age than those drinking milk seldom or never. INTRODUCTION: The role of lifelong milk consumption for bone mineral density (BMD) and bone mineral content (BMC) in old age is not clear. Here we assess the association between hip BMD and BMC in old age and milk consumption in adolescence, midlife, and current old age. METHODS: Participants of the Age, Gene/Environment Susceptibility-Reykjavik Study, aged 66-96 years (N = 4,797), reported retrospective milk intake during adolescence and midlife as well as in current old age, using a validated food frequency questionnaire. BMC of femoral neck and trochanteric area was measured by volumetric quantitative computed tomography and BMD obtained. Association was assessed using linear regression models. Differences in BMC, bone volume, and BMD in relation to milk intake were portrayed as gender-specific Z-scores. RESULTS: Men consuming milk ≥ once/day during midlife had 0.21 higher Z-scores for BMD and 0.18 for BMC in femoral neck (95 % confidence interval 0.05-0.39 and 0.01-0.35, respectively) compared with < once/week. Results were comparable for trochanter. For women the results were similar, with slightly lower differences according to midlife milk consumption. For current and adolescent milk consumption, differences in Z-scores were smaller and only reached statistical significance in the case of BMD for current consumption in men, while this association was less pronounced for BMC. CONCLUSIONS: Our data suggest that regular milk consumption throughout life, from adolescence to old age, is associated with higher BMC and BMD in old age, with no differences seen in bone volume. The strongest associations are seen for midlife milk consumption in both genders.

Low blood pressure and antihypertensive treatment are independently associated with physical and mental health status in patients with arterial disease: the SMART study.

OBJECTIVE: To investigate the independent effects of antihypertensive treatment and blood pressure (BP) levels on physical and mental health status in patients with arterial disease. DESIGN AND SETTING: Cross-sectional analyses were conducted within the single-centre Secondary Manifestations of ARTerial disease (SMART) study, in a hospital care setting. SUBJECTS: A total of 5877 patients (mean age 57 years) with symptomatic and asymptomatic arterial disease underwent standardized vascular screening. MAIN OUTCOME MEASURE: The primary outcome was self-rated physical and mental health assessed using the 36-item short-form health survey. RESULTS: In the total population, antihypertensive drug use and increased intensity of antihypertensive treatment were associated with poorer health status independent of important confounders including BP levels; adjusted mean differences [95% confidence interval (CI)] in physical and mental health between n = 0 and n ≥ 3 antihypertensives were -1.2 (-2.1; -0.3) and -3.5 (-4.4; -2.6), respectively. Furthermore, both lower systolic and lower diastolic BP levels were related to poorer physical and mental health status independent of antihypertensive treatment. Mean differences (95% CI) in physical and mental health status per SD decrease in systolic BP were -0.56 (-0.84; -0.27) and -0.32 (-0.61; -0.03) and per SD decrease in diastolic BP were -0.50 (-0.78; -0.23) and -0.08 (-0.36; 0.20), respectively. The association between low BP and poor health status was particularly present in patients with coronary artery disease. CONCLUSIONS: In a population of patients with asymptomatic and symptomatic arterial disease, antihypertensive treatment and lower BP levels are independently associated with poorer self-rated physical and mental health. These findings suggest that different underlying mechanisms may explain these independent associations.

Associations of current and remitted major depressive disorder with brain atrophy: the AGES-Reykjavik Study.

BACKGROUND: To examine whether lifetime DSM-IV diagnosis of major depressive disorder (MDD), including age at onset and number of episodes, is associated with brain atrophy in older persons without dementia. METHOD: Within the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, 4354 persons (mean age 76 ± 5 years, 58% women) without dementia had a 1.5-T brain magnetic resonance imaging (MRI) scan. Automated brain segmentation total and regional brain volumes were calculated. History of MDD, including age at onset and number of episodes, and MDD in the past 2 weeks was diagnosed according to DSM-IV criteria using the Mini-International Neuropsychiatric Interview (MINI). RESULTS: Of the total sample, 4.5% reported a lifetime history of MDD; 1.5% had a current diagnosis of MDD (including 75% with a prior history of depression) and 3.0% had a past but no current diagnosis (remission). After adjusting for multiple covariates, compared to participants never depressed, those with current MDD (irrespective of past) had more global brain atrophy [B = -1.25%, 95% confidence interval (CI) -2.05 to -0.44], including more gray- and white-matter atrophy in most lobes, and also more atrophy of the hippocampus and thalamus. Participants with current, first-onset MDD also had more brain atrophy (B = -1.62%, 95% CI -3.30 to 0.05) whereas those remitted did not (B = 0.06%, 95% CI -0.54 to 0.66). CONCLUSIONS: In older persons without dementia, current MDD, irrespective of prior history, but not remitted MDD was associated with widespread gray- and white-matter brain atrophy. Prospective studies should examine whether MDD is a consequence of, or contributes to, brain volume loss and development of dementia.

Retinopathy in old persons with and without diabetes mellitus: the Age, Gene/Environment Susceptibility--Reykjavik Study (AGES-R).

AIMS/HYPOTHESIS: We aimed to describe the prevalence of retinopathy in an aged cohort of Icelanders with and without diabetes mellitus. METHODS: The study population consisted of 4,994 persons aged ≥ 67 years, who participated in the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-R). Type 2 diabetes mellitus was defined as HbA(1c) ≥ 6.5% (>48 mmol/mol). Retinopathy was assessed by grading fundus photographs using the modified Airlie House adaptation of the Early Treatment Diabetic Retinopathy Study protocol. Associations between retinopathy and risk factors were estimated using odds ratios obtained from multivariate analyses. RESULTS: The overall prevalence of retinopathy in AGES-R was 12.4%. Diabetes mellitus was present in 516 persons (10.3%), for 512 of whom gradable fundus photos were available, including 138 persons (27.0%, 95% CI 23.2, 31.0) with any retinopathy. Five persons (1.0%, 95% CI 0.3, 2.3) had proliferative retinopathy. Clinically significant macular oedema was present in five persons (1.0%, 95% CI 0.3, 2.3). Independent risk factors for retinopathy in diabetic patients in a multivariate model included HbA(1c), insulin use and use of oral hypoglycaemic agents, the last two being indicators of longer disease duration. In 4478 participants without diabetes mellitus, gradable fundus photos were available for 4,453 participants, with retinopathy present in 476 (10.7%, 95% CI 9.8, 11.6) and clinically significant macular oedema in three persons. Independent risk factors included increasing age and microalbuminuria. CONCLUSIONS/INTERPRETATION: Over three-quarters (78%) of retinopathy cases were found in persons without diabetes and a strong association between microalbuminuria and non-diabetic retinopathy was found. These results may have implications for patient management of the aged.

Lifelong physical activity in maintaining bone strength in older men and women of the Age, Gene/Environment Susceptibility-Reykjavik Study.

UNLABELLED: We examined if lifelong physical activity is important for maintaining bone strength in the elderly. Associations of quantitative computerized tomography-acquired bone measures (vertebral and femoral) and self-reported physical activity in mid-life (mean age, 50 years), in old age (≥65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. Results conclude lifelong physical activity with continuation into old age (≥65 years) best maintains better bone health later in life. INTRODUCTION: Skeletal loading is thought to modulate the loss of bone in later life, and physical activity is a chief means of affecting bone strength by skeletal loading. Despite much discussion regarding lifelong versus early adulthood physical activity for preventing bone loss later in life, inconsistency still exists regarding how to maintain bone mass later in life (≥65 years). METHODS: We examined if lifelong physical activity is important for maintaining bone strength in the elderly. RESULTS: The associations of quantitative computerized tomography-acquired vertebral and femoral bone measures and self-reported physical activity in mid-life (mean age, 50 years), in old age (≥65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. CONCLUSION: Our findings conclude that lifelong physical activity with continuation into old age (≥65 years) best maintains better bone health in the elderly.

Dynamics between psychological distress and body mass index throughout adult life; evidence from 3 large cohort studies.

BACKGROUND: Associations between body mass index (BMI) and psychological distress (PD) have been reported; however, few longitudinal studies have accounted for likely life-course differences in BMI and PD stability, consistency, and their interplay across time. METHODS: Via random intercepts cross-lagged panel models, we assessed the predictive effects (from BMI to PD or vice-versa) across the last two centuries in the Coronary Artery Risk Development in Young Adults [CARDIA, beginning in 1985-6] study using the Center for Epidemiological Studies-Depression Scale [CES-D], and in the National Child Development Study [NCDS, beginning in 1958] and British Cohort Study [BCS, beginning in 1970] using the Malaise Inventory [MI]), assessed at least 4 times in adult life. FINDINGS: In CARDIA (n = 4724), NCDS58 (n = 7149) and BCS70 (n = 5967), autoregressive effects were stronger for BMI than for PD, meaning that carry-over effects from one occasion to the next were larger for BMI than for PD. Small interindividual correlations between traits of higher BMI and higher PD were identified among females (rfemale<|0·2|) but not males (rmale<|0·03|) in CARDIA and NCDS. Cross-lagged effects were very weak or close to zero (standardized effects η<|0·1|). INTERPRETATION: In the United States, depressive symptoms and BMI were positively correlated at the trait level among females. In the United Kingdom, relationships between PD and BMI were inconsistent between generations, with effect sizes of unlikely clinical importance, indicating negligible dominance of an intraindividual effect of BMI on PD or vice versa.

Migraine is associated with an increased risk of deep white matter lesions, subclinical posterior circulation infarcts and brain iron accumulation: the population-based MRI CAMERA study.

Previous studies have suggested that migraine is a risk factor for brain lesions, but methodological issues hampered drawing definite conclusions. Therefore, we initiated the magnetic resonance imaging (MRI) 'CAMERA' (Cerebral Abnormalities in Migraine, an Epidemiological Risk Analysis) study. We summarize our previously published results. A total of 295 migraineurs and 140 controls were randomly selected from a previously diagnosed population-based sample (n = 6039), who underwent an interview, physical examination and a brain MRI scan. Migraineurs, notably those with aura, had higher prevalence of subclinical infarcts in the posterior circulation [odds ratio (OR) 13.7; 95% confidence interval (CI) 1.7, 112]. Female migraineurs were at independent increased risk of white matter lesions (WMLs; OR 2.1; 95% CI 1.0, 4.1), and migraineurs had a higher prevalence of brainstem hyperintense lesions (4.4% vs. 0.7%, P = 0.04). We observed a higher lifetime prevalence of (frequent) syncope and orthostatic insufficiency in migraineurs; future research needs to clarify whether autonomic nervous system dysfunction could explain (part of) the increased risk of WMLs in female migraineurs. Finally, in migraineurs aged < 50 years, compared with controls, we found evidence of increased iron concentrations in putamen (P = 0.02), globus pallidus (P = 0.03) and red nucleus (P = 0.03). Higher risks in those with higher attack frequency or longer disease duration were found consistent with a causal relationship between migraine and lesions. This summary of our population-based data illustrates that migraine is associated with a significantly increased risk of brain lesions. Longitudinal studies are needed to assess whether these lesions are progressive and have relevant (long-term) functional correlates.

The interaction of adiposity with the CRP gene affects CRP levels: age, gene/environment susceptibilty-Reykjavik study.

OBJECTIVE: Common diseases often have an inflammatory component reflected by associated markers such as serum C-reactive protein (CRP) levels. Circulating CRP levels have also been associated with adipose tissue as well as with specific CRP genotypes. We examined the interaction between measures of body mass index (BMI), waist circumference and fat percent (total fat measured by bioimpedance) with genotypes of the CRP gene in the determination of CRP levels. METHODS: The first 2296 participants (mean age 76+/-6 years, 42% men) in the Age, Gene/Environment Susceptibility-Reykjavik Study, a multidisciplinary epidemiological study to determine risk factors in aging, were genotyped for 10 single nucleotide polymorphisms (SNPs) in the CRP gene. General linear models with age and terms for interaction of CRP genotypes with BMI, waist circumference and percent fat were used to evaluate the association of genotypes to CRP levels (high-sensitivity method, range 0-10 mg l(-1)) in men and women separately. RESULTS: We focused on the SNP rs1205 that represents the allele that captures the strongest effects of the gene on CRP levels. Carriers of the rs1205 G allele had significantly higher CRP levels than noncarriers in a dose-dependent manner. Compared to the AA genotype, the slope of the increase in CRP with increasing BMI (P=0.045) and waist circumference (P=0.014) was different for the G allele carriers and of similar magnitude in both men and women. The rs1205 interactions were not significant for fat mass percent, suggesting a possible association with fat localization. CONCLUSIONS: This study further illuminates the known association between measures of adiposity and CRP levels and is shown to be dependent on variation in the rs1205 SNP of the CRP gene. The correlated increase in CRP levels with adiposity is accentuated by presence of the G allele.

Iron accumulation in deep brain nuclei in migraine: a population-based magnetic resonance imaging study.

A small magnetic resonance imaging (MRI) study showed increased iron depositions in the periaqueductal grey matter in migraineurs, suggestive of a disturbed central antinociceptive neuronal network. With 1.5-T MRI, we assessed iron concentrations in seven deep brain nuclei in a large population-based cohort. We compared T2 values between migraineurs (n = 138) and controls (n = 75), with multivariate regression analysis. Analyses were conducted in age strata (< 50, n = 112; > or = 50) because iron measures are increasingly influenced by non-iron-related factors in the older group. Overall, migraineurs and controls did not differ, nor did migraineurs with vs. without aura. In the younger migraineurs compared with controls, T2 values were lower in the putamen (P = 0.02), globus pallidus (P = 0.03) and red nucleus (P = 0.03). Similarly, in these younger migraineurs, controlling for age, those with longer migraine history had lower T2 values in the putamen (P = 0.01), caudate (P = 0.04) and red nucleus (P = 0.001). Repeated migraine attacks are associated with increased iron concentration/accumulation in multiple deep nuclei that are involved in central pain processing and migraine pathophysiology. It remains unclear whether iron accumulation in the antinociceptive network has a causative role in the development of (chronic) migraine headache.

C-reactive protein in migraine sufferers similar to that of non-migraineurs: the Reykjavik Study.

C-reactive protein (CRP), a marker of inflammation, has been associated with cardiovascular disease. Risk of cardiovascular disease is increased in migraineurs with aura. Results from a clinical report, case-control and a cohort study suggest that CRP is elevated in migraineurs compared with non-migraineurs. We examined the proposed association in a case-control study nested within two large population-based studies. The relationship between migraine and CRP (high-sensitivity CRP) was studied in 5906 men and women aged 55.0 +/- 8.5 years in the Reykjavik Study and 1345 men and women aged 27.7 +/- 5.5 years from the Reykjavik Study for the Young. A modified version of the International Headache Society's criteria was used to categorize people into migraineurs (two or more symptoms) or non-migraineurs. Migraineurs with visual or sensory symptoms were further defined as having migraine with aura (MA) or without aura (MO). Multivariable-adjusted CRP levels were similar in migraineurs and non-migraineurs for men (0.83 vs. 0.79 mg/l, P = 0.44) and for women (0.87 vs. 0.87 mg/l, P = 0.90). When further stratified by migraine aura and age, no differences were found between non-migraineurs, MO and MA among men. In women, CRP levels were borderline higher in those with MO compared with non-migraineurs and those with MA (1.01 mg/l vs. 0.81 and 0.75 mg/l, P = 0.08 and P = 0.08) in age group 19-34 years, but significantly lower in age group 60-81 years (0.52 mg/l vs. 1.07 and 1.01 mg/l, P = 0.007 and P = 0.03). CRP levels were not increased among migraine sufferers compared with non-migraineurs. Older women migraineurs without aura had lower CRP values than non-migraineurs and migraineurs with aura.

White Matter Lesion Penumbra Shows Abnormalities on Structural and Physiologic MRIs in the Coronary Artery Risk Development in Young Adults Cohort.

BACKGROUND AND PURPOSE: White matter lesions are 1 age-related manifestation of cerebrovascular disease, but subthreshold abnormalities have been identified in nonlesional WM. We hypothesized that structural and physiologic MR imaging findings of early cerebrovascular disease can be measured in middle-aged subjects in tissue adjacent to WM lesions, termed "penumbra." MATERIALS AND METHODS: WM lesions were defined using automated segmentation in 463 subjects, 43-56 years of age, from the Coronary Artery Risk Development in Young Adults (CARDIA) longitudinal observational cohort study. We described 0- to 2-mm and 2- to 4-mm-thick spatially defined penumbral WM tissue ROIs as rings surrounding WM lesions. The remaining WM was defined as distant normal-appearing WM. Mean signal intensities were measured for FLAIR, T1-, and T2-weighted images, and from fractional anisotropy, mean diffusivity, CBF, and vascular reactivity maps. Group comparisons were made using Kruskal-Wallis and pair-wise t tests. RESULTS: Lesion volumes averaged 0.738 ± 0.842 cm3 (range, 0.005-7.27 cm3). Mean signal intensity for FLAIR, T2, and mean diffusivity was increased, while T1, fractional anisotropy, and CBF were decreased in white matter lesions versus distant normal-appearing WM, with penumbral tissues showing graded intermediate values (corrected P < .001 for all group/parameter comparisons). Vascular reactivity was significantly elevated in white matter lesions and penumbral tissue compared with distant normal-appearing white matter (corrected P ≤ .001). CONCLUSIONS: Even in relatively healthy 43- to 56-year-old subjects with small white matter lesion burden, structural and functional MR imaging in penumbral tissue reveals significant signal abnormalities versus white matter lesions and other normal WM. Findings suggest that the onset of WM injury starts by middle age and involves substantially more tissue than evident from focal white matter lesions visualized on structural imaging.

Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location.

BACKGROUND AND PURPOSE: Incidental foci of signal loss suggestive of cerebral microbleeds (CMBs) are frequent findings on gradient echo T2* weighted MRI (T2* MRI) of patients with haemorrhagic or ischaemic stroke. There are few prevalence data on older populations. This paper reports on the prevalence and location of CMBs in a community based cohort of older men and women (born 1907-1935) who participated in the Age Gene/Environment Susceptibility (AGES)-Reykjavik Study, a population based cohort study that followed the Reykjavik Study METHODS: As part of the examination, all eligible and consenting cohort members underwent a full brain MRI, and blood was drawn for genotyping. Results are based on the first 1962 men (n = 820) and women (n = 1142), mean age 76 years, with complete MRI and demographic information available. RESULTS: Evidence of CMBs was found in 218 participants (11.1% (95% CI 9.8% to 12.6%)); men had significantly more CMBs than women (14.4% vs 8.8%; p = 0.0002, age adjusted). The prevalence of CMBs increased with age (p = 0.0001) in both men (p = 0.006) and women (p = 0.007). CMBs were located in the cerebral lobes (70%), the basal ganglia region (10.5%) and infratentorium (18.6%). Having a CMB was significantly associated with a homozygote Apo E epsilon4epsilon4 genotype (p = 0.01). CONCLUSION: Cerebral microbleeds are common in older persons. The association with homozygote Apo E epsilon4 genotype and finding a relative predominance in the parietal lobes might indicate an association with amyloid angiopathy.