Evaluating Prophylactic Effect of Bovine Colostrum on Intestinal Barrier Function in Zonulin Transgenic Mice: A Transcriptomic Study.

The intestinal barrier comprises a single layer of epithelial cells tightly joined to form a physical barrier. Disruption or compromise of the intestinal barrier can lead to the inadvertent activation of immune cells, potentially causing an increased risk of chronic inflammation in various tissues. Recent research has suggested that specific dietary components may influence the function of the intestinal barrier, potentially offering a means to prevent or mitigate inflammatory disorders. However, the precise mechanism underlying these effects remains unclear. Bovine colostrum (BC), the first milk from cows after calving, is a natural source of nutrients with immunomodulatory, anti-inflammatory, and gut-barrier fortifying properties. This novel study sought to investigate the transcriptome in BC-treated Zonulin transgenic mice (Ztm), characterized by dysbiotic microbiota, intestinal hyperpermeability, and mild hyperactivity, applying RNA sequencing. Seventy-five tissue samples from the duodenum, colon, and brain of Ztm and wild-type (WT) mice were dissected, processed, and RNA sequenced. The expression profiles were analyzed and integrated to identify differentially expressed genes (DEGs) and differentially expressed transcripts (DETs). These were then further examined using bioinformatics tools. RNA-seq analysis identified 1298 DEGs and 20,952 DETs in the paired (Ztm treatment vs. Ztm control) and reference (WT controls) groups. Of these, 733 DEGs and 10,476 DETs were upregulated, while 565 DEGs and 6097 DETs were downregulated. BC-treated Ztm female mice showed significant upregulation of cingulin (Cgn) and claudin 12 (Cldn12) duodenum and protein interactions, as well as molecular pathways and interactions pertaining to tight junctions, while BC-treated Ztm males displayed an upregulation of transcripts like occludin (Ocln) and Rho/Rac guanine nucleotide exchange factor 2 (Arhgf2) and cellular structures and interfaces, protein-protein interactions, and organization and response mechanisms. This comprehensive analysis reveals the influence of BC treatment on tight junctions (TJs) and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling pathway gene expressions. The present study is the first to analyze intestinal and brain samples from BC-treated Ztm mice applying high-throughput RNA sequencing. This study revealed molecular interaction in intestinal barrier function and identified hub genes and their functional pathways and biological processes in response to BC treatment in Ztm mice. Further research is needed to validate these findings and explore their implications for dietary interventions aimed at improving intestinal barrier integrity and function. The MGH Institutional Animal Care and Use Committee authorized the animal study (2013N000013).

[Migraine prevalence, migraine incidence and migraine drug prescriptions in primary care in the capital region of Iceland].

INTRODUCTION: The study aim was to describe migraine incidence over the ten-year periods, 2000-2009 and 2010-2019, in individuals aged 10-79 years in primary healthcare centre (PHCC) Sólvangur and Fjörður, Hafnarfirði. Another aim was to estimate migraine prevalence in primary care clinics in the capital area of Iceland over the period 2010-2019 and describe prescriptions for migraine specific drugs and other drugs used for migraine. MATERIAL AND METHODS: This is a retrospective study based on data from medical records from the primary care clinics of the capital region of Iceland. The cohort consisted of individuals aged 10-79 years who were diagnosed with migraine, G43 according to the ICD-10 classification system. RESULTS: Migraine incidence at age 10-79 years over the ten-year period 2000-2009 at the primary care clinic Sólvangur was estimated 3.4 cases per 1000 person-years, during the period 2010-2019 in both Sólvangur and Fjörður clinics migraine incidence was estimated 2.9 cases per 1000 person-years. Increase was shown between the two periods in prescriptions of triptan drugs, opioids, and beta-blockers, where two-thirds of the migraineurs got prescription over the two periods. Women were three times more likely to be diagnosed with migraine than men, but men were diagnosed at younger age than women. Migraine prevalence at age 10-79 years in PHCCs in the capital area of Iceland was 4.4% over the period 2010-2019. CONCLUSION: Migraine prevalence in the PHCCs of the capital area of Iceland was only one third of migraine prevalence in the population-based cohort pilot study Heilsusaga Íslendinga. Increase in opioid drug prescriptions for individuals diagnosed with migraine is of concern and needs further study.

Structured headache services as the solution to the ill-health burden of headache: 1. Rationale and description

In countries where headache services exist at all, their focus is usually on specialist (tertiary) care. This is clinically and economically inappropriate: most headache disorders can effectively and more efficiently (and at lower cost) be treated in educationally supported primary care. At the same time, compartmentalizing divisions between primary, secondary and tertiary care in many health-care systems create multiple inefficiencies, confronting patients attempting to navigate these levels (the "patient journey") with perplexing obstacles.High demand for headache care, estimated here in a needs-assessment exercise, is the biggest of the challenges to reform. It is also the principal reason why reform is necessary.The structured headache services model presented here by experts from all world regions on behalf of the Global Campaign against Headache is the suggested health-care solution to headache. It develops and refines previous proposals, responding to the challenge of high demand by basing headache services in primary care, with two supporting arguments. First, only primary care can deliver headache services equitably to the large numbers of people needing it. Second, with educational supports, they can do so effectively to most of these people. The model calls for vertical integration between care levels (primary, secondary and tertiary), and protection of the more advanced levels for the minority of patients who need them. At the same time, it is amenable to horizontal integration with other care services. It is adaptable according to the broader national or regional health services in which headache services should be embedded.It is, according to evidence and argument presented, an efficient and cost-effective model, but these are claims to be tested in formal economic analyses.

The prevalence of hypnic headache in Iceland.

OBJECTIVE: To determine the prevalence of hypnic headache. BACKGROUND: The exact prevalence of hypnic headache is unknown since there are no published population-based prevalence studies. METHODS: This study was a pilot for the SAGA cohort study, a population-based study on life stressors and various indices of health. Of 1398 invited adults, 921 (66%) participated; 402 men (average age 45.6 years, SD 13.2) and 519 women (52.6 years, SD 11.1). Subjects answered a headache questionnaire including a screening question for hypnic headache. "Do you have a headache that occurs only during sleep and causes wakening?". Diagnosis of hypnic headache was made by clinical interview using ICHD-3 criteria. RESULTS: Among 921 participants, six screened positive for hypnic headache, of those two 0.22% (95% CI 0.06-0.79%) had probable hypnic headache and none had definite hypnic headache. CONCLUSION: Confirming that hypnic headache is rare, these data suggest a 0.22% prevalence of probable hypnic headache.

Multimorbidity and use of hypnotic and anxiolytic drugs: cross-sectional and follow-up study in primary healthcare in Iceland.

BACKGROUND: The prevalence of multimorbidity is increasing worldwide, presumably leading to an increased use of medicines. During the last decades the use of hypnotic and anxiolytic benzodiazepine derivatives and related drugs has increased dramatically. These drugs are frequently prescribed for people with a sleep disorder often merely designated as "insomnia" in the medical records and lacking a clear connection with the roots of the patients' problems. Our aim was to analyse the prevalence of multimorbidity in primary healthcare in Iceland, while concurrently investigating a possible association with the prevalence and incidence of hypnotic/anxiolytic prescriptions, short-term versus chronic use. METHODS: Data were retrieved from a comprehensive database of medical records from primary healthcare in Iceland to find multimorbid patients and prescriptions for hypnotics and anxiolytics, linking diagnoses (ICD-10) and prescriptions (2009-2012) to examine a possible association. Nearly 222,000 patients, 83 % being local residents in the capital area, who contacted 16 healthcare centres served in total by 140 general practitioners, were set as a reference to find the prevalence of multimorbidity as well as the prevalence and incidence of hypnotic/anxiolytic prescriptions. RESULTS: The prevalence of multimorbidity in the primary care population was 35 %, lowest in the young, increasing with age up to the 80+ group where it dropped somewhat. The prevalence of hypnotic/anxiolytic prescriptions was 13.9 %. The incidence rate was 19.4 per 1000 persons per year in 2011, and 85 % of the patients prescribed hypnotics/anxiolytics were multimorbid. Compared to patients without multimorbidity, multimorbid patients were far more likely to be prescribed a hypnotic and/or an anxiolytic, OR = 14.9 (95 % CI = 14.4-15.4). CONCLUSIONS: Patients with multiple chronic conditions are common in the primary care setting, and prevalence and incidence of hypnotic/anxiolytic prescriptions are high. Solely explaining use of these drugs by linear thinking, i.e. that "insomnia" leads to their prescription is probably simplistic, since the majority of patients prescribed these drugs are multimorbid having several chronic conditions which could lead to sleeping problems. However, multimorbidity as such is not an indication for hypnotics, and doctors should be urged to greater caution in their prescribing, bearing in mind non-pharmacological therapy options.

Lack of association between the MTHFR C677T variant and migraine with aura in an older population: could selective survival play a role?

BACKGROUND: Several studies, but not all, of primarily middle-aged or younger adults have suggested that the common MTHFR C677T variant is a genetic risk factor for migraine with aura (MA). Here, we consider whether this variant is associated with MA risk in an older non-clinical population (AGES-Reykjavik cohort). METHODS: Participants are a sub-sample ( N = 1976) of subjects from the Reykjavik Study (RS; mean age 50) and its continuation, AGES-RS (mean age 76). We estimated the relative odds of MA in TT versus CC carriers using multinomial logistic regression. As both MA and the TT genotype may be linked with modestly reduced longevity, we performed a simple simulation to illustrate the effect that selective survival may have had on our observed gene-disease association. RESULTS: TT versus CC carriers were at marginally reduced odds of MA (ORTT 0.55 (0.3-1.0), P = 0.07), significantly for women (ORTT 0.45 (0.2-0.9), P = 0.03). Assuming the 'true' (e.g. mid-life) effect of the TT genotype is ORTT 1.26, from a recent meta-analysis, our simulation suggested that if 25-year mortality had been (hypothetically) 13% higher in MA subjects with the TT versus CC genotype, the measured effect of the TT genotype on MA would have been attenuated to non-significance (e.g. ORTT 1.00). Our observed protective effect was consistent with the most extreme selective mortality scenario, in which essentially all of the previously reported increased mortality in MA subjects was (hypothetically) found in CT or TT carriers. CONCLUSION: The MTHFR 677TT genotype was associated with marginally reduced risk of MA in our older population. Our simulation illustrated how even modest selective survival might obscure the apparent effect of a genetic or other risk factor in older populations. We speculate that some of the heterogeneity previously observed for this particular genetic variant may be due to age range differences in the studied populations.

Use of benzodiazepines and benzodiazepine-related drugs in the Nordic countries between 2000 and 2020.

Use of benzodiazepines (BZ) and related drugs is subject to considerable debate due to problems with dependency and adverse events. We aimed to describe and compare their use across the Nordic countries. Data on the use of clonazepam, BZ-sedatives, BZ-hypnotics, and benzodiazepine-related drugs (BZRD) in adults (≥20 years) were obtained from nationwide registers in Denmark, Finland, Iceland, Norway, and Sweden, 2000-2020. Main measures were therapeutic intensity (TI:DDD/1000 inhabitants [inhab.]/day) and annual prevalence (users/1000 inhab./year). Overall, TI of BZ and related drugs decreased in all Nordic countries from 2004 to 2020. However, there were considerable differences between countries in TI. In 2020, the TI of BZ and related drugs ranged from 17 DDD/1000 inhab./day in Denmark to 93 DDD/1000 inhab./day in Iceland. BZRD accounted for 55-78% of BZ use in 2020, followed by BZ sedatives at 20-44%, BZ-hypnotics at <1-5%, and clonazepam at <1-2%. Annual prevalence of BZ use increased with age in all countries, and the highest annual prevalence was observed among people ≥80 years. Overall, the use of BZ and related drugs has decreased in all Nordic countries from 2004 to 2020, however, with considerable differences in their use between countries. The highest prevalence was observed among the oldest age groups-despite warnings against their use in this population.

Meals, Microbiota and Mental Health in Children and Adolescents (MMM-Study): A protocol for an observational longitudinal case-control study.

Recent studies indicate that the interplay between diet, intestinal microbiota composition, and intestinal permeability can impact mental health. More than 10% of children and adolescents in Iceland suffer from mental disorders, and rates of psychotropics use are very high. The aim of this novel observational longitudinal case-control study, "Meals, Microbiota and Mental Health in Children and Adolescents (MMM-Study)" is to contribute to the promotion of treatment options for children and adolescents diagnosed with mental disorders through identification of patterns that may affect the symptoms. All children and adolescents, 5-15 years referred to the outpatient clinic of the Child and Adolescent Psychiatry Department at The National University Hospital in Reykjavik, Iceland, for one year (n≈150) will be invited to participate. There are two control groups, i.e., sex-matched children from the same postal area (n≈150) and same parent siblings (full siblings) in the same household close in age +/- 3 years (n<150). A three-day food diary, rating scales for mental health, and multiple questionnaires will be completed. Biosamples (fecal-, urine-, saliva-, blood samples, and buccal swab) will be collected and used for 16S rRNA gene amplicon sequencing of the oral and gut microbiome, measurements of serum factors, quantification of urine metabolites and host genotype, respectively. For longitudinal follow-up, data collection will be repeated after three years in the same groups. Integrative analysis of diet, gut microbiota, intestinal permeability, serum metabolites, and mental health will be conducted applying bioinformatics and systems biology approaches. Extensive population-based data of this quality has not been collected before, with collection repeated in three years' time, contributing to the high scientific value. The MMM-study follows the "Strengthening the Reporting of Observational Studies in Epidemiology" (STROBE) guidelines. Approval has been obtained from the Icelandic National Bioethics Committee, and the study is registered with Clinicaltrials.gov. The study will contribute to an improved understanding of the links between diet, gut microbiota and mental health in children through good quality study design by collecting information on multiple components, and a longitudinal approach. Furthermore, the study creates knowledge on possibilities for targeted and more personalized dietary and lifestyle interventions in subgroups. Trial registration numbers: VSN-19-225 & NCT04330703.

Prophylactic Effect of Bovine Colostrum on Intestinal Microbiota and Behavior in Wild-Type and Zonulin Transgenic Mice.

The microbiota-gut-brain axis (MGBA) involves bidirectional communication between intestinal microbiota and the gastrointestinal (GI) tract, central nervous system (CNS), neuroendocrine/neuroimmune systems, hypothalamic-pituitary-adrenal (HPA) axis, and enteric nervous system (ENS). The intestinal microbiota can influence host physiology and pathology. Dysbiosis involves the loss of beneficial microbial input or signal, diversity, and expansion of pathobionts, which can lead to loss of barrier function and increased intestinal permeability (IP). Colostrum, the first milk from mammals after birth, is a natural source of nutrients and is rich in oligosaccharides, immunoglobulins, growth factors, and anti-microbial components. The aim of this study was to investigate if bovine colostrum (BC) administration might modulate intestinal microbiota and, in turn, behavior in two mouse models, wild-type (WT) and Zonulin transgenic (Ztm)-the latter of which is characterized by dysbiotic microbiota, increased intestinal permeability, and mild hyperactivity-and to compare with control mice. Bioinformatics analysis of the microbiome showed that consumption of BC was associated with increased taxonomy abundance (p = 0.001) and diversity (p = 0.004) of potentially beneficial species in WT mice and shifted dysbiotic microbial community towards eubiosis in Ztm mice (p = 0.001). BC induced an anxiolytic effect in WT female mice compared with WT female control mice (p = 0.0003), and it reduced anxiogenic behavior in Ztm female mice compared with WT female control mice (p = 0.001), as well as in Ztm male mice compared with WT BC male mice (p = 0.03). As evidenced in MGBA interactions, BC supplementation may well be applied for prophylactic approaches in the future. Further research is needed to explore human interdependencies between intestinal microbiota, including eubiosis and pathobionts, and neuroinflammation, and the potential value of BC for human use. The MGH Institutional Animal Care and Use Committee authorized the animal study (2013N000013).

Body weight changes and longitudinal associations with cognitive decline among community-dwelling older adults.

INTRODUCTION: We aim to investigate the longitudinal associations between changes in body weight (BW) and declines in cognitive function and risk of mild cognitive impairment (MCI)/dementia among cognitively normal individuals 65 years or older. METHODS: Data from the Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik Study) including 2620 participants, were examined using multiple logistic regression models. Cognitive function included speed of processing (SP), executive function (EF), and memory function (MF). Changes in BW were classified as; weight loss (WL), weight gain (WG), and stable weight (SW). RESULTS: Mean follow-up time was 5.2 years and 61.3% were stable weight. Participants who experienced WL (13.4%) were significantly more likely to have declines in MF and SP compared to the SW group. Weight changes were not associated with EF. WL was associated with a higher risk of MCI, while WG (25.3%) was associated with a higher dementia risk, when compared to SW. DISCUSSION: Significant BW changes in older adulthood may indicate impending changes in cognitive function.

Zonulin-Dependent Intestinal Permeability in Children Diagnosed with Mental Disorders: A Systematic Review and Meta-Analysis.

Worldwide, up to 20% of children and adolescents experience mental disorders, which are the leading cause of disability in young people. Research shows that serum zonulin levels are associated with increased intestinal permeability (IP), affecting neural, hormonal, and immunological pathways. This systematic review and meta-analysis aimed to summarize evidence from observational studies on IP in children diagnosed with mental disorders. The review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search of the Cochrane Library, PsycINFO, PubMed, and the Web of Science identified 833 records. Only non-intervention (i.e., observational) studies in children (<18 years) diagnosed with mental disorders, including a relevant marker of intestinal permeability, were included. Five studies were selected, with the risk of bias assessed according to the Newcastle-Ottawa scale (NOS). Four articles were identified as strong and one as moderate, representing altogether 402 participants providing evidence on IP in children diagnosed with attention deficit and hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). In ADHD, elevated serum zonulin levels were associated with impaired social functioning compared to controls. Children with ASD may be predisposed to impair intestinal barrier function, which may contribute to their symptoms and clinical outcome compared to controls. Children with ASD, who experience gastro-intestinal (GI) symptoms, seem to have an imbalance in their immune response. However, in children with OCD, serum zonulin levels were not significantly different compared to controls, but serum claudin-5, a transmembrane tight-junction protein, was significantly higher. A meta-analysis of mean zonulin plasma levels of patients and control groups revealed a significant difference between groups (p = 0.001), including the four studies evaluating the full spectrum of the zonulin peptide family. Therefore, further studies are required to better understand the complex role of barrier function, i.e., intestinal and blood-brain barrier, and of inflammation, to the pathophysiology in mental and neurodevelopmental disorders. This review was PROSPERO preregistered, (162208).

Migraine headache in middle age and late-life brain infarcts.

CONTEXT: Migraine is considered to be an episodic condition with no long-term consequences. However, recent studies suggest that migraine attacks may be associated with pathologic changes in the brain, particularly in the cerebellum. OBJECTIVE: To determine whether individuals not reporting headache compared with individuals reporting migraine symptoms, particularly aura, in midlife are at increased risk of late-life infarct-like lesions found on magnetic resonance imaging (MRI) without consideration of clinical symptoms. DESIGN, SETTING, AND PARTICIPANTS: A population-based study of men and women in Reykjavik, Iceland (cohort born 1907-1935; n = 4689; 57% women) were followed up since 1967, examined, and interviewed about migraine symptoms in midlife (mean age, 51 years; range, 33-65 years). Between 2002 and 2006, more than 26 years later, brain MRIs were performed. Participants reporting headaches once or more per month were asked about migraine symptoms including nausea, unilateral location, photophobia, visual disturbance, and numbness. These individuals with headache were classified as having migraine without aura, migraine with aura, or nonmigraine headache. A comprehensive cardiovascular risk assessment was performed at both examinations. MAIN OUTCOME MEASURE: Presence of infarct-like lesions (total) and specifically located in the cortical, subcortical, and cerebellar regions. RESULTS: Infarct-like lesions were present in 39.3% of men and 24.6% of women. After adjusting for age, sex, and follow-up time, compared with those not reporting headaches once or more per month (n = 3243), those with midlife migraine with aura (n = 361) had an increased risk of late-life infarct-like lesions (adjusted odds ratio [OR], 1.4; 95% confidence interval [CI], 1.1-1.8) that specifically reflected an association with cerebellar lesions in women (prevalence of infarcts 23.0% for women with migraine with aura vs 14.5% for women not reporting headaches; adjusted OR, 1.9; 95% CI, 1.4-2.6 vs a 19.3% prevalence of infarcts for men with migraine with aura vs 21.3% for men not reporting headaches; adjusted OR, 1.0; 95% CI, 0.6-1.8; P<.04 for interaction by sex). Migraine without aura and nonmigraine headache were not associated with an increased risk. CONCLUSIONS: Migraine with aura in midlife was associated with late-life prevalence of cerebellar infarct-like lesions on MRI. This association was statistically significant only for women. This is consistent with the hypothesis that migraine with aura in midlife is associated with late-life vascular disease in the cerebellum and in women.

Validity of self-reports and drug use among young people seeking treatment for substance abuse or dependence.

The present study assessed drug use and the validity of self-reports of drug use among young people seeking treatment. On admission the participants (n = 316), 215 males and 101 females, were interviewed about their drug use. Urine samples were collected to screen for alcohol, amphetamine, benzodiazepines, cannabis, cocaine, methylenedioxymethamphetamine (MDMA) and opiate use. Self-reports of substance use were compared with urinalysis results. Seventy-three percent of the participants reported use of two or more substances. Single substance users were primarily alcohol users. Kappa agreement between self-report and urinalysis results was of acceptable concordance (> or = 0.65) except for alcohol (kappa = 0.19). Conditional kappa values were good (> or = 0.85) with exception of opiates (cond. kappa = 0.57). The self-reports were generally reliable among young people seeking treatment. No significant differences (p > or = 0.54) were found in the validity of self-reports between the genders.

Midlife migraine and late-life parkinsonism: AGES-Reykjavik study.

OBJECTIVE: In the present study, we tested the hypothesis that having migraine in middle age is related to late-life parkinsonism and a related disorder, restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED). METHODS: The AGES-Reykjavik cohort (born 1907-1935) has been followed since 1967. Headaches were classified based on symptoms assessed in middle age. From 2002 to 2006, 5,764 participants were reexamined to assess symptoms of parkinsonism, diagnosis of Parkinson disease (PD), family history of PD, and RLS/WED. RESULTS: Subjects with midlife migraine, particularly migraine with aura (MA), were in later life more likely than others to report parkinsonian symptoms (odds ratio [OR]MA = 3.6 [95% CI 2.7-4.8]) and diagnosed PD (ORMA = 2.5 [95% CI 1.2-5.2]). Women with MA were more likely than others to have a parent (ORMA = 2.26 [95% CI 1.3-4.0]) or sibling (ORMA = 1.78 [95% CI 1.1-2.9]) with PD. Late-life RLS/WED was increased for headache generally. Associations were independent of cardiovascular disease and MRI-evident presumed ischemic lesions. CONCLUSIONS: These findings suggest there may be a common vulnerability to, or consequences of, migraine and multiple indicators of parkinsonism. Additional genetic and longitudinal observational studies are needed to identify candidate pathways that may account for the comorbid constellation of symptoms.

Migraine, depression, and brain volume: the AGES-Reykjavik Study.

OBJECTIVE: To examine the joint association of migraine headache and major depressive disorder on brain volume in older persons without dementia. METHODS: Participants (n = 4,296, 58% women) from the population-based Age, Gene/Environment Susceptibility-Reykjavik Study were assessed for migraine headache in 1967-1991 (age 51 years [range 33-65]) according to modified International Classification of Headache Disorders-II criteria. In 2002-2006 (age 76 years [range 66-96]), lifetime history of major depressive disorder (depression) was diagnosed according to DSM-IV criteria, and full-brain MRI was acquired, which was computer postprocessed into total brain volume (TBV) (gray matter [GM], white matter [WM], white matter hyperintensities) and CSF volume for each study subject. We compared brain tissue volumes by headache categories with or without depression using linear regression, adjusting for intracranial volume and other factors. RESULTS: Compared with the reference group (no headache, no depression) TBV and WM and GM volumes were smaller in those with both migraine and depression (TBV -19.2 mL, 95% confidence interval [CI] -35.3, -3.1, p = 0.02; WM -12.8 mL, CI -21.3, -4.3, p = 0.003; GM -13.0 mL, CI -26.0, 0.1, p = 0.05) but not for those with migraine alone (TBV 0.4 mL, WM 0.2 mL, GM 0.6 mL) or depression alone (TBV -3.9 mL, WM -0.9 mL, GM -2.9 mL). CONCLUSIONS: Reporting both migraine and major depressive disorder was associated with smaller brain tissue volumes than having one or neither of these conditions. Migraineurs with depression may represent a distinct clinical phenotype with different long-term sequelae. Nonetheless, the number of subjects in the current study is relatively small and these findings need to be confirmed in future studies.

Migraine with aura and risk of cardiovascular and all cause mortality in men and women: prospective cohort study.

OBJECTIVE: To estimate whether migraine in mid-life is associated with mortality from cardiovascular disease, other causes, and all causes. DESIGN: Population based cohort study. SETTING: Reykjavik, Iceland. PARTICIPANTS: 18,725 men and women, born 1907-35 and living in Reykjavik and adjacent communities. MAIN OUTCOME MEASURES: Mortality from cardiovascular disease, non-cardiovascular disease, and all causes. Questionnaires and clinical measures were obtained in mid-life (mean age 53, range 33-81) in the Reykjavik Study (1967-91). Headache was classified as migraine without aura, migraine with aura, or non-migraine headache. Median follow-up was 25.9 years (0.1-40.2 years), with 470,990 person years and 10,358 deaths: 4323 from cardiovascular disease and 6035 from other causes. We used Cox regression to estimate risk of death in those with migraine compared with others, after adjusting for baseline risk factors. RESULTS: People with migraine with aura were at increased risk of all cause mortality (adjusted (for sex and multivariables) hazard ratio 1.21, 95% confidence interval 1.12 to 1.30) and mortality from cardiovascular disease (1.27, 1.13 to 1.43) compared with people with no headache, while those with migraine without aura and non-migraine headache were not. Further examination of mortality from cardiovascular disease shows that people with migraine with aura were at increased risk of mortality from coronary heart disease (1.28, 1.11 to 1.49) and stroke (1.40, 1.10 to 1.78). Women with migraine with aura were also at increased risk of mortality from non-cardiovascular disease (1.19, 1.06 to 1.35). CONCLUSIONS: Migraine with aura is an independent risk factor for cardiovascular and all cause mortality in men and women. The risk of mortality from coronary heart disease and stroke mortality is modestly increased in people with migraine, particularly those with aura.

Hypertension control as predictor of mortality in treated men and women, followed for up to 30 years.

PURPOSE: To examine the prognosis of treated, hypertensive individuals in the Reykjavik Study. METHODS: A population-based longitudinal study of 9328 men and 10 062 women. Subjects were included in the study during the period 1967-1996. Two groups of treated, hypertensive subjects were defined at baseline: with controlled blood pressure and with uncontrolled blood pressure. Main outcome measures were cardiovascular disease (CVD) mortality and all-cause mortality. RESULTS: Of the hypertensive men 24.8% were treated, and of those 38.3% were controlled, and of the hypertensive women 45.3% were treated, and of those 52.7% were controlled. Comparing treated and uncontrolled (systolic blood pressure (SBP) > or =160 mmHg and/or diastolic blood pressure (DBP) > or =95 mmHg) versus treated and controlled hypertensive subjects, followed for up to 30 years, the uncontrolled men and women were at significantly higher risk of CVD mortality, hazard ratio (HR) = 1.47 (95% confidence interval (CI): 1.06-2.02) and HR 1.70 (CI: 1.23-2.36), respectively, showing the benefit of hypertension control. The risk of all-cause mortality was increased for treated, uncontrolled men and women, compared with those who were treated and controlled, but did not reach significance. When analyzing blood pressure as a continuous variable among treated, hypertensive subjects, SBP was a better predictor than DBP of CVD mortality and all-cause mortality in women. This was not the case in men. CONCLUSIONS: Control of blood pressure among hypertensive-treated subjects at baseline was associated with a lower risk of CVD mortality during follow-up. SBP was the single best predictor of CVD mortality and all-cause mortality in treated women. The uncontrolled women were at a higher risk than the uncontrolled men.