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Background: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. Methods: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. Results: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20–1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01–1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59–0.67) to 0.65 (95% CI, 0.62–0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=−4.82×10 −3 per year [95% CI, −6.49×10 −3 to −3.14×10 −3 ]; P =1.82×10 −8 ), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86–0.98]; P =0.0041). Conclusions: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Purpose The purpose of this study is to investigate the use of a VR Headset in routine clinical practice as an additional source of information for patients with diabetic macular edema (DME) and their companions. Methods Survey including 121 patients with DME, 22 companions, and 14 healthcare professionals from 8 ophthalmology centers in Germany. Patients’ and their companions’ health literacy was assessed by questionnaires including knowledge statements before and after watching a VR-based 3-D educational video. HCPs’ perspectives on the usability of a VR Headset were also assessed. Results Patients’ mean age was 63.4 ± 12.2 years, 64.5% were men, and 76% (92/121) had previous anti-VEGF (VEGF, vascular endothelial growth factor) injections. After using the VR Headset, over 85% of patients and companions felt better informed about DME and its treatment. Patients’ mean (± SD) number of correct answers to knowledge statements increased from 13.2 ± 3.7 before to 15.5 ± 2.3 after using the VR Headset. Over 95% of patients and companions rated content and ease of understanding of the video as “very good” or “good.” Most patients and all companions considered the use of a VR Headset as a positive experience, most wishing to obtain information via VR Headset in the future. Most physicians and all medical assistants rated the effect of the VR Headset on patient satisfaction as positive and suggested further VR modules. Conclusion After using the VR Headset, patients with DME and their companions demonstrated knowledge gains that may be meaningful individually and contribute to better adherence. This may offer an additional opportunity for knowledge transfer.

BACKGROUND Despite effective treatment options, chronic kidney disease (CKD) has become a major cause of mortality worldwide due to the ever-increasing number of patients with type 2 diabetes mellitus (T2DM). Guideline-compliant, at least, annual screening of patients with T2DM is crucial to prevent renal disease progression. However, data on the prevalence of CKD in patients with T2DM and on screening frequency are limited. SMART-Finder is the first study to exclusively use data provided directly by patients via an adherence app to collect information on the prevalence of CKD, risk factors, disease management, and quality of life of patients with T2DM in Germany. OBJECTIVE The primary objective of this study is to determine the proportion of patients with T2DM and an elevated urine albumin-to-creatinine ratio (UACR; albumin-to-creatinine ratio stage A2 and A3) at baseline and after 12 (±3) months. Secondary objectives include the proportion of patients who remain in or switch to another albumin-to-creatinine ratio classification category after 12 months, information on quality of life, disease awareness, and adherence rates, as well as the proportion of patients without any UACR-screening data. Recruitment occurs via push notification among MyTherapy app users with T2DM. METHODS This is a single-arm, retrospective/prospective, observational, digital, patient-centered cohort study, with recruitment and data documentation via a health app. Required routine laboratory data are provided by treating physicians to their patients for data entry. The study population includes adult patients with T2DM documenting their data in the MyTherapy app using their own smartphone or tablet. Study participants are provided with a specifically developed electronic case report form containing questions on demographic and general data, quality of life, disease awareness, and laboratory values including estimated glomerular filtration rate, UACR, hemoglobin 1Ac, and blood pressure. Apart from demographic and general data, all data are collected at baseline and 12 months after the last UACR assessment. An automatically generated push notification reminds participants of the second data entry. The extracted and pseudonymized data are analyzed descriptively. RESULTS The enrollment period for this study started in February 2023 and shall end after 12 months or after the enrollment of 5000 patients. An interim analysis is planned 3 months after the inclusion of the first patient and the final analysis after 12 months of follow-up. CONCLUSIONS Overall, the study will contribute to minimizing the existing data gap on the prevalence of CKD in patients with T2DM in Germany, provide important insights into the current disease management of patients with T2DM in everyday clinical practice in Germany, and support guideline-based care for the participating patients. CLINICALTRIAL INTERNATIONAL REGISTERED REPORT PRR1-10.2196/44996

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Introduction The aim of this study was to examine physicians' preferences regarding adherence-promoting programs (APPs), and to investigate which APP characteristics influence the willingness of physicians to implement these in daily practice. Materials and Methods A discrete choice experiment was conducted among general practitioners, cardiologists, neurologists and ophthalmologists in Germany. The design considered five attributes with two or three attribute levels each: validation status of the APP; possibility for physicians to receive a certificate; type of intervention; time commitment per patient and quarter of the year to carry out the APP; reimbursement for APP participation, per included patient and quarter of the year.A multinomial logit model was run to estimate physicians' utility for each attribute and to evaluate the influence of different levels on the probability of choosing a specific APP. The relative importance of the attributes was compared between different pre-defined subgroups. Results In total, 222 physicians were included in the analysis. The most important characteristics of APPs were time commitment to carry out the program (34.8% importance), reimbursement (33.3%), and validation status of the program (23.7%). The remaining attributes (type of intervention: 3.6%; possibility to receive a certificate: 4.7%) were proven to be less important for a physician's decision to participate in an APP. Physicians on average preferred APP alternatives characterized by little time commitment (β=1.456, p

BACKGROUND The BETACONNECT autoinjector and myBETAapp app were designed to support patients with multiple sclerosis receiving interferon β-1b and are an ideal platform for digital observational studies. A recent pilot study in Germany demonstrated the feasibility of using the app to recruit patients, obtain informed consent, and evaluate medication-taking behavior over 6 months. OBJECTIVE This study aims to describe medication-taking behavior for 1 year in patients with multiple sclerosis receiving interferon β-1b based on data collected from the app and to provide information on patient-reported outcomes (PROs). The optional use of the cognitive training tool PEAK (Peak, formerly Brainbow Ltd) is included to test the feasibility of gamification in this setting. METHODS A prospective and retrospective, exploratory, digital, observational cohort study was conducted among users of the app in Germany. Invitations to participate were sent to patients’ apps between February and May 2019. Participants provided electronic informed consent. Injection-related data from consenting patients’ devices were collected prospectively for 1 year following the consent date and retrospectively for ≤1 year from the first day of use (if historical data were available). Participants also completed three electronic PRO instruments every 3 months: the EuroQol 5-Dimension, 5-Level questionnaire (EQ-5D-5L); the Treatment Satisfaction Questionnaire for Medication (TSQM; version II); and a questionnaire on satisfaction with treatment support (on a server accessed via an emailed hyperlink). All patients were offered optional access to the professional version of PEAK. RESULTS Of 1778 registered app accounts (May 2019), 79 patients (4.44%) provided informed consent; 62 (3.49%) were eligible for inclusion in the prospective analysis, of whom, 60 (97%) also had retrospective data. The mean age of the 62 participants was 43.2 (SD 11.5) years and 41 (66%) were women. Compliance over the 1-year prospective observational period (primary end point) was high (median 98.9%, IQR 94.3%-100%) and similar among men and women. Persistence and adherence (coprimary end points) decreased from 85% (53/62) and 74% (46/62), respectively, at 6 months to 76% (47/62) and 65% (40/62), respectively, at 12 months; both were higher in men than in women. A retrospective analysis showed similar patterns. The PRO questionnaires were answered by 79% (49/62) of the participants at baseline and 50% (31/62) of them at month 12. Women had more severe problems in some EQ-5D-5L dimensions (mobility, usual activities, and pain/discomfort) and lower median convenience scores on the TSQM (version II) than men. At month 12, 84% (26/31) of the patients were satisfied or very satisfied with the app. PEAK was used by 67% (14/21) of men and 49% (20/41) of women. CONCLUSIONS This study showed high compliance and decreasing persistence and adherence over 1 year and demonstrated the feasibility of including remotely completed electronic PRO instruments in digital observational studies.

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association ( GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms ( SNPs) significantly associated with migraine risk ( P

Background Sleep disorders and fatigue are common in multiple sclerosis (MS). The underlying causes are not fully understood, and prospective studies are lacking. Therefore, we conducted a prospective, observational cohort study investigating sleep quality, fatigue, quality of life, and comorbidities in patients with MS. Methods Patients with relapsing-remitting MS or clinically isolated syndrome treated with interferon beta-1b were followed over two years. The primary objective was to investigate correlations between sleep quality (PSQI), fatigue (MFIS), and functional health status (SF-36). Secondary objectives were to investigate correlations of sleep quality and daytime sleepiness (ESS), depression (HADS-D), anxiety (HADS-A), pain (HSAL), and restless legs syndrome (RLS). We applied descriptive statistics, correlation and regression analyses. Results 139 patients were enrolled, 128 were available for full analysis. The proportion of poor sleepers (PSQI≥5) was 55.47% at the beginning and 37.70% by the end of the study (106 and 41 evaluable questionnaires, respectively). Poor sleepers performed worse in MFIS, SF-36, ESS, HADS-D, and HADS-A scores. The prevalence of patients with RLS was low (4.5%) and all were poor sleepers. Poor sleep quality was positively correlated with fatigue and low functional health status. These relationships were corroborated by multivariable-adjusted regression analyses. ESS values and poor sleep quality at baseline seem to predict sleep quality at the one-year follow-up. No variable predicted sleep quality at the two-year follow-up. Conclusions Our results confirm the high prevalence of poor sleep quality among patients with MS and its persistent correlation with fatigue and reduced quality of life over time. They highlight the importance of interventions to improve sleep quality. Trial registration The study was registered at clinicaltrials.gov: NCT01766063 (registered December 7, 2012). Registered retrospectively (first patient enrolled December 6, 2012). Electronic supplementary material The online version of this article (10.1186/s12883-018-1113-5) contains supplementary material, which is available to authorized users.

Background Accurate measurement of medication adherence using classical observational studies typically depends on patient self-reporting and is often costly and slow. In contrast, digital observational studies that collect data directly from the patient may pose minimal burden to patients while facilitating accurate, timely, and cost-efficient collection of real-world data. In Germany, ~80% of patients with multiple sclerosis (MS) treated with interferon beta 1b (Betaferon) use an electronic autoinjector (BETACONNECT), which automatically records every injection. Patients may also choose to use a medical app (myBETAapp) to document injection data and their well-being (using a “wellness tracker” feature). Objective The goal of this pilot study was to establish a digital study process that allows the collection of medication usage data and to assess medication usage among patients with MS treated with interferon beta-1b who use myBETAapp. Methods The PROmyBETAapp digital observational study was a mixed prospective and retrospective, noninterventional, cohort study conducted among users of myBETAapp in Germany (as of December 2017: registered accounts N=1334; actively used accounts N=522). Between September and December 2017, users received two invitations on their app asking them to participate. Interested patients were provided detailed information and completed an electronic consent process. Data from consenting patients’ devices were collected retrospectively starting from the first day of usage if historical data were available in the database and collected prospectively following consent attainment. In total, 6 months of data on medication usage behavior were collected along with 3 months of wellness tracker data. Descriptive statistics were used to analyze persistence, compliance, and adherence to therapy. Results Of the 1334 registered accounts, 96 patients (7.2%) provided informed consent to participate in the study. Of these, one patient withdrew consent later. For another patient, injection data could not be recorded during the study period. Follow-up of the remaining 94 patients ended in May 2018. The mean age of participants was 46.6 years, and 50 (53%) were female. Over the 6-month study period, persistence with myBETAapp usage was 96% (90/94), mean compliance was 94% of injections completed, and adherence (persistence and ≥80% compliance) was 89% (84/94). There was no apparent difference between male and female participants and no trend across age groups. The wellness tracker was used by 21% of participants (20/94), with a mean of 3.1 entries per user. Conclusions This study provides important information on medication usage among patients with MS treated with interferon beta-1b and on consenting behavior of patients in digital studies. In future studies, this approach may allow patients’ feedback to be rapidly implemented in existing digital solutions. Trial Registration ClinicalTrials.gov NCT03134573; https://clinicaltrials.gov/ct2/show/NCT03134573

Adherence to long-term treatment in chronic diseases such as multiple sclerosis is challenging. Many disease-modifying drugs (DMDs) for MS need to be injected. Injection devices may improve satisfaction with the injection procedure and boost adherence. Meeting patients’ needs in handling and design of autoinjectors and other supporting elements may be key to successful therapy. The BETACONNECT™ system is a platform-based approach in DMD therapy. It combines autoinjector technology with digital tools to support patient self-management and facilitate communication between patients and healthcare providers. Here, we describe the components of the BETACONNECT system and review data on patients’ satisfaction with the BETACONNECT autoinjector and how it compares to other devices. Additionally, we present first data on patients’ satisfaction with the myBETAapp™.

Background Maintaining patient adherence to disease modifying drugs in multiple sclerosis is a challenge, which can be improved by autoinjectors. The BETACONNECT® is a fully electronic autoinjector for the injection of interferon beta-1b (IFN beta-1b) automatically recording injections. Methods The BETAEVAL study was a prospective, observational, cohort study over 24 weeks among patients with relapsing remitting multiple sclerosis or clinically isolated syndrome treated with IFN beta-1b in Germany using the BETACONNECT®. The primary aim was to investigate treatment adherence, secondary aims included assessing satisfaction and functional health status. Adherence was evaluated from injection data recorded by the device. Patient-related data were obtained from clinical examinations and patient questionnaires. Results Of the 151 patients enrolled, 143 were available for analysis. Thirty-four patients discontinued the study prematurely. 107/143 (74.8%) patients still used the BETACONNECT® at the end of the study. Injection data from the device at any visit was available for 107 patients. Among those, the percentage of adherent patients injecting ≥80% of doses and still participating in the study was 57.9% at week 24. 29% of patients prematurely stopped the study, 13.1% injected

Background Restless legs syndrome (RLS) is increasingly being reported as a comorbidity of migraine. Methods We conducted a systematic review and meta-analysis of studies investigating RLS in headache/migraine and vice versa. We calculated the prevalence and 95% confidence intervals (CI) of RLS in headache/migraine, of headache/migraine in RLS and controls, and odds ratios (ORs) of the association between the conditions. We then determined pooled effect estimates for the associations. Results We identified 24 studies. RLS prevalence in migraine ranged from 8.7% to 39.0% with no apparent differences based on gender and aura status. Prevalence among controls was compatible with the literature. Migraine prevalence in RLS ranged from 15.1% to 62.6%. We did not pool prevalence data because of high unexplained heterogeneity. High heterogeneity with respect to the association between any migraine and RLS could be explained by study design. Pooled analyses showed substantially higher effect estimates in case-control studies (pooled OR = 4.19, 95% CI 3.07–5.71; I 2 = 0.0%) than in cohort studies (pooled OR = 1.22, 95% CI 1.14–1.30; I 2 = 0.0%). Conclusion Our results support the concept of RLS as an important comorbidity of migraine. However, the degree of association appears to be strongly determined by study design. Potential effects by gender and aura status and the role of RLS in other headache disorders remain unclear.

Background and Purpose— Previous research suggests greater risk of coronary heart disease with lower levels of the adrenal steroid dehydroepiandrosterone sulfate (DHEAS). No studies have examined the association between DHEAS and risk of ischemic stroke. DHEAS may influence ischemic stroke risk through atherosclerotic-related mechanisms (endothelial function and smooth muscle cell proliferation) or insulin resistance. Methods— Between 1989 and 1990, 32 826 women without prior stroke in the Nurses’ Health Study, an observational cohort, provided blood samples and were followed up for cardiovascular events. Among this sample, using a nested case–control design, 461 ischemic strokes were confirmed by medical records by 2006. Cases were matched to controls free of stroke at the time of the index case and by age, race, menopausal status, postmenopausal hormone use, smoking status, and date of sample collection. Multivariable conditional logistic regression was used. Results— Median DHEAS levels did not differ between cases (median=58.7) and controls (median=66.0; P =0.10). Conditional on matching factors, the lowest DHEAS quartile exhibited a relative risk of 1.30 for ischemic stroke (95% confidence interval, 0.88–1.94), compared with the highest quartile and marginally unchanged when adjusted for confounders (relative risk=1.33; 95% confidence interval, 0.87–2.02). When modeled as a binary variable dichotomized at the lowest quartile, women with low DHEAS (≤the lowest quartile) had a significantly increased multivariable adjusted risk of ischemic stroke compared with those with higher levels (relative risk=1.41; 95% confidence interval, 1.03–1.92). Conclusions— Lower DHEAS levels were associated with a greater risk of ischemic stroke, even after adjustment for potential confounders. These novel observations warrant confirmation in other populations.

Background While cross-sectional studies have shown associations between migraine and depression, few studies have been able to evaluate the association between migraine and incident depression. Methods A prospective cohort study among 36,016 women without a history of depression enrolled in the Women's Health Study who provided information about migraine and headache at baseline. Women were classified as either having nonmigraine headache, migraine with aura, migraine without aura, past history of migraine or no history of headache. Cox proportional hazards models were used to evaluate the association between migraine and headache status and incident depression. Results At baseline, 5115 women reported a history of nonmigraine headache, 1805 reported migraine with aura, 2723 reported migraine without aura, and 1896 reported a past history of migraine. During 13.8 mean years of follow-up, 3833 new cases of depression occurred. The adjusted relative risks of incident depression were 1.44 (95% CI: 1.32, 1.56) for nonmigraine headache, 1.53 (95% CI: 1.35, 1.74) for migraine with aura, 1.40 (95% CI: 1.25, 1.56) for migraine without aura, and 1.56 (95% CI: 1.37, 1.77) for past history of migraine compared to no history of headache. Conclusions Middle-aged women with migraine or nonmigraine headache are at increased risk of incident depression. Frequent migraine attacks (weekly or daily) were associated with the highest risk for developing depression.

Background and purpose Telomere shortening has been implicated in cardiovascular disease (CVD). However, prospective data on the association between relative telomere length (RTL) and ischaemic stroke are scarce and inconclusive. Methods We used a nested case–control design among women participating in the prospective Nurses' Health Study. Participants provided blood samples in 1990 and were followed till 2006. Women with confirmed incident ischaemic stroke were matched to controls by age, smoking, postmenopausal status and postmenopausal hormone use. Quantitative polymerase chain reaction was used to determine RTL in genomic DNA extracted from peripheral blood leukocytes. Conditional logistic regression was used to determine the risk of ischaemic stroke associated with RTL, using RTL quartiles and as dichotomous according to the median. Results Data on RTL were available from 504 case–control pairs. Results did not suggest an association between RTL and ischaemic stroke. The odds ratio (OR) for ischaemic stroke was 0.82 [95% confidence interval (CI) 0.52–1.32] comparing lowest with the highest RTL quartile and 0.90 (95% CI 0.65–1.24) comparing RTL below the median with RTL above the median. Associations were unchanged after additional adjustment for cardiovascular risk factors. Further analyses suggested an association between RTL and fatal ischaemic stroke (54 case–control pairs; lowest versus highest quartile OR = 1.99, 95%CI 0.26–14.9); however, results were statistically insignificant. Conclusion In this large nested case–control study among women RTL was not associated with ischaemic stroke. In light of the varying study results in the literature on the association between telomere length and stroke, additional research is warranted.

Background: Few clinic-based studies report an association between migraine and restless legs syndrome (RLS); however, population-based data are unavailable. Methods: Cohort study among 31,370 women participating in the Women’s Health Study. We had detailed self-reported information on migraine, including aura status, and RLS. RLS was ascertained at the 9-year follow-up. We calculated odds ratios (OR) and 95% confidence intervals (CI) for the association between migraine and RLS. We investigated any indication of migraine until RLS ascertainment as well as migraine with and without aura at baseline, prior migraine before baseline, and new reports of migraine during follow-up. Results: At baseline or during follow-up 6857 (21.9%) women reported any migraine. These women had an increased risk for RLS (multivariable-adjusted OR = 1.22; 95%CI 1.13–1.32). Further analyses indicated a similar association for migraine with aura (multivariable-adjusted OR = 1.27; 95%CI 1.10–1.48) and migraine without aura (multivariable-adjusted OR = 1.24; 95%CI 1.09–1.40) as well as for new reports of migraine during follow-up (multivariable-adjusted OR = 1.30; 95%CI 1.10–1.54). Prior migraine did not appear to be associated with RLS. Conclusions: Our data suggest an association between migraine and RLS at the population level. The association is similar for migraine with and without aura and for new reports of migraine during follow-up.

Aims: Migraine has a wide clinical spectrum. Our aim was to group information on migraine characteristics into meaningful components and to identify key components of the migraine phenotype. Methods: We performed two principal component analyses, one among participants in the Women’s Health Study enrollment cohort and one in a sub-cohort with additional migraine-specific information. Results: Among the 9427 women with migraine attack–related information at enrollment, the three most important components pertained to central nervous system (CNS) sensitization, attack frequency/pain location and aura/visual phenomena. In the subgroup of 1675 women with more detailed information, food triggers and unspecific symptoms constituted two principal components that explain more of the variance of the migraine phenotype than the three attack–related components. Conclusions: Our results indicate that information on migraine-associated features, symptoms and triggers is highly correlated, allowing the extraction of principal components. Migraine attack–related symptoms are best summarized by symptoms related to CNS sensitization, attack frequency/pain location and aura/visual phenomena. Taking a more general view, unspecific symptoms and food triggers appear to carry stronger importance in characterizing the migraine phenotype. These components are useful for future research on the pathophysiology and genetics of migraine and may have implications for diagnosing and treating patients.

(Headache 2011;51:201-207) Background.— An association between the 677C>T polymorphism (rs1801133) in the methylenetetrahydrofolate reductase gene (MTHFR) and cluster headache is plausible, but has not been investigated. Objective.— To investigate this association among Caucasians. Methods.— Case–control study among 147 cluster headache patients and 599 population-based age- and gender-matched controls. Cluster headache was diagnosed according to the criteria of the International Headache Society. Genotypes of the MTHFR 677C>T polymorphism were detected by restriction fragment length polymorphism analysis. We used logistic regression analysis to investigate the association between cluster headache and genotypes with additive, dominant, and recessive models. We considered a Bonferroni-corrected P value T polymorphism and cluster headache overall. Subgroup analyses suggested that carriers of the MTHFR 677T allele may have an increased risk for chronic cluster headache. This may be regarded as hypothesis-generating and should be further investigated in independent studies.

(Headache 2010;50:588-599) Background.— Data on the association between the MTHFR 677C>T and ACE D/I polymorphisms and migraine including aura status are conflicting. Objective.— The objective of this study is to perform a systematic review and meta-analysis on this topic. Methods.— We searched for studies published until March 2009 using electronic databases (MEDLINE, EMBASE, Science Citation Index) and reference lists of studies and reviews on the topic. Assessment for eligibility of studies and extraction of data was performed by 2 independent investigators. For each study we calculated the odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs. Results.— Thirteen studies investigated the association between the MTHFR 677C>T polymorphism and migraine. The TT genotype was associated with an increased risk for any migraine, which only appeared for migraine with aura (pooled OR = 1.48, 95% CI 1.02-2.13), but not for migraine without aura. Nine studies investigated the association of the ACE D/I polymorphism with migraine. The II genotype was associated with a reduced risk for migraine with aura (pooled OR = 0.71, 95% CI 0.55-0.93) and migraine without aura (pooled OR = 0.84, 95% CI 0.70-0.99). Results for both variants were driven by studies in non-Caucasian populations. Results among Caucasians did not suggest an association. Extractable data did not allow investigation of gene–gene interactions. Conslusions.— The MTHFR 677TT genotype is associated with an increased risk for migraine with aura, while the ACE II genotype is protective against both migraine with and without aura. Results for both variants appeared only among non-Caucasian populations. There was no association among Caucasians.

Background and methods: Data on the association between the SLC6A4 5-HTTLPR polymorphism and migraine are conflicting. We performed a systematic review and meta-analysis among studies published up to September 2009. For each study with genotype information, we calculated odds ratios (OR) and 95% confidence intervals (CI) assuming additive, dominant, and recessive genetic models. We then calculated pooled ORs and 95% CIs. Results: Among the ten studies identified there was no overall association between the polymorphism and any migraine for Europeans or Asians. However, European women carrying the S allele had an increased risk for any migraine (dominant model: pooled OR = 2.02; 95% CI 1.24–3.28). Results among Europeans further suggested an increased risk for migraine with aura among carriers of the S/S genotype (recessive model: pooled OR = 1.41; 95% CI 0.83–2.40). Conclusions: While our results indicate no overall association between the SLC6A4 5-HTTLPR polymorphism and migraine among Europeans and Asians, gender and migraine aura status may have modifying roles among Europeans.

Migraine is a common headache disorder that is increasingly being evaluated in population-based studies. The American Migraine Study II and the Women's Health Study (WHS) have successfully used ‘modified’ International Classification of Headache Disorders, 1st edition (ICHD-I) criteria to classify patients. Investigating agreement of self-reported migraine in large epidemiological studies with the criteria of the revised version [International Classification of Headache Disorders, 2nd edition (ICHD-II)] is sparse. We have investigated 1675 women with self-reported migraine participating in the WHS, who provided additional information on a detailed migraine questionnaire that allowed us to apply all ICHD-II criteria. In this sub-cohort, we confirmed self-reported migraine in > 87% of women when applying the ICHD-II criteria for migraine (71.5%) and probable migraine without aura (16.2%). In conclusion, there is excellent agreement between self-reported migraine and ICHD-II-based migraine classification in the WHS. In addition, questionnaire-based migraine assessment according to full ICHD-II criteria in large population-based studies is feasible.

Population-based studies have established an association between migraine and cardiovascular disease (CVD). We sought to investigate whether genetic variants implicated in CVD are associated with migraine. We performed an association study among 25,713 women participating in the Women's Health Study, with information on 77 previously characterized polymorphisms. Migraine and migraine aura status were self-reported. We used logistic regression to investigate the genotype-migraine association. At baseline, 4705 (18.3%) women reported history of migraine; 39.6% of the 3306 women with active migraine indicated aura. Regarding any history of migraine, the multivariable-adjusted odds ratios (95% confidence intervals) for TNF rs673 were 0.52 (0.30 to 0.89), for TGFB1 rs1800469 0.93 (0.89 to 0.98), and for CCR2 rs1799864 1.12 (1.03 to 1.21). Among active migraine with aura, the odds ratios (95% confidence intervals) were 1.35 (1.0 to 1.81) for TNF rs1800750, 1.13 (1.02 to 1.26) for TNF rs1800629, and 1.22 (1.07 to 1.40) for CCR2 rs1799864 ; among active migraine without aura, 0.9 (0.84 to 0.97) for TGFB1 rs1800469 , 1.13 (1.01 to 1.27) for NOS3 rs3918226 , and 1.12 (1.02 to 1.24) for IL9 rs2069885 . After correction for multiple testing using the false discovery rate, none of the results remained significant. Our data suggest an association of polymorphisms implicated in inflammatory pathways and migraine in women. TNF , CCR2, TGFB1, NOS3, and IL9 warrant further investigation. Perspective This article presents results from an association study of 77 polymorphisms, implicated in CVD, and migraine. Variants in TNF, CCR2, TGFB1, NOS3, and IL9 were found to be associated with migraine but did not remain significant after adjustment for multiple testing. Variations in these genes warrant further investigation.

Interrelationships among the ACE deletion/insertion (D/I) polymorphism (rs1799752), migraine, and cardiovascular disease (CVD) are biologically plausible but remain controversial.Association study among 25,000 white US women, participating in the Women's Health Study, with information on the ACE D/I polymorphism. Migraine and migraine aura status were self-reported. Incident CVD events were confirmed after medical record review. We used logistic regression to investigate the genotype-migraine association and proportional hazards models to evaluate the interrelationship among genotype, migraine, and incident CVD.At baseline, 4,577 (18.3%) women reported history of migraine; 39.5% of the 3,226 women with active migraine indicated aura. During 11.9 years of follow-up, 625 CVD events occurred. We did not find an association of the ACE D/I polymorphism with migraine or migraine aura status. There was a lack of association between the ACE D/I polymorphism and incident major CVD, ischemic stroke, and myocardial infarction. Migraine with aura doubled the risk for CVD, but only for carriers of the DD (multivariable-adjusted relative risk [RR] = 2.10; 95% CI = 1.22-3.59; p = 0.007) and DI genotype (multivariable-adjusted RR = 2.31; 95% CI = 1.52-3.51; p0.0001). The risk was not significant among carriers of the II genotype, a pattern we observed for myocardial infarction and ischemic stroke.Data from this large cohort of women do not suggest an association of the ACE deletion/insertion (D/I) polymorphism with migraine, migraine aura status, or cardiovascular disease (CVD). The increased risk for CVD among migraineurs with aura was only apparent for carriers of the DD/DI genotype. Due to limited number of outcome events, however, future studies are warranted to further investigate this association.

Objective.— To investigate the role of three common polymorphisms in the β2-adrenoceptor gene in migraine. Background.— Migraine has been associated with increased risk of cardiovascular disease and asthma in which β2-adrenoceptors play an important role; β-adrenoceptor antagonists are used in migraine prevention. However, the role of variants in the β2-adrenoceptor gene in migraine is unclear. Methods.— Association study among 23,753 white women, participating in the Women's Health Study, for whom we had information on migraine at baseline and genotype status of the polymorphisms rs1042713 (Gly16Arg), rs1042714 (Gln27Glu), rs1800888 (Thr164Ile). Migraine was self-reported and we distinguished between any history of migraine, active migraine with and without aura, and prior migraine (history of migraine but not active migraine) in our analyses. Results.— At baseline 4339 women reported any history of migraine. Of these, 3041 had active migraine (1221 migraine with aura, 1820 migraine without aura) and 1298 prior migraine. No migraine was reported by 19,414 women. Genotype- and haplotype-based analyses did not show an association of any of the gene variants tested with any history of migraine. The multivariable-adjusted odds ratios (ORs) (95% confidence intervals) for any history of migraine in the additive model were 1.0 (0.96-1.05) for rs1042713, 1.0 (0.95-1.05) for rs1042714, and 0.84 (0.68-1.05) for rs1800888. In the haplotype analysis the ORs ranged from 0.83 (0.67-1.03) to 1.01 (0.94-1.07) with Gly16-Glu27-Thr164 as the reference. We also did not find associations in the genotype- and haplotype-based analyses within migraine-specific subgroups. Conclusions.— Our results do not support a role of 3 investigated polymorphisms in the β2-adrenoceptor gene in migraine pathophysiology.

Recent findings suggest an association between the renin-angiotensin system and migraine. However, genetic studies are scarce and controversial.To investigate the association between the AGTR1 1166AC and AGT Met235Thr polymorphisms with migraine and migraine aura status.We performed an association study among 25,000 Caucasian US women, participating in the Women's Health Study, with information on the AGTR1 1166AC and AGT Met235Thr polymorphisms. Migraine and migraine aura status were self-reported. We distinguished between any history of migraine, active migraine with aura, active migraine without aura, and prior migraine (history of migraine, but not in the year prior to baseline). We used logistic regression to investigate the genotype-migraine association.At baseline, 4577 (18.3%) women reported any history of migraine; 39.5% of the 3226 women with active migraine indicated aura. The polymorphisms were not associated with migraine or migraine-specific subgroups. We also did not find a significant interaction between the polymorphisms.Data from this large cohort of Caucasian women do not suggest an association of polymorphisms in the renin-angiotensin system with migraine or aura status. Future studies should focus on haplotype analyses and additional gene-gene as well as gene-environment interactions.

CASE HISTORY This 50-year-old white man has a 5-year history of headaches described as an 8/10 in intensity stabbing in the left temple and sometimes around the left ear associated with tearing and redness of the left eye, congestion of the left nares, and light and noise sensitivity but no aura. During a headache, he prefers to sit or lie down. Without treatment, the headache lasts about 2 hours. Since the onset, the headache has been triggered almost all of the time by alcoholic beverages with the onset 30-45 minutes later. Perhaps one time per year the headache occurs spontaneously. The headaches have been triggered by drinking white or red wine, margaritas, beer, vodka, and grappa. Every evening, he usually drinks 3 margaritas and 2 glasses of Chardonnay and occasionally other alcoholic beverages. He does not drink at other times of the day. About twice a month, he has 6 or more drinks. He scores a 16 on the Alcohol Use Disorders Identification Test (AUDIT). (A score of 8 or more indicates a strong likelihood of hazardous or harmful alcohol consumption in adult populations.) The headaches are invariably triggered by lesser and greater amounts of alcohol intake. The headache goes away in about 30 minutes if he takes zolmitriptan 5 mg nasal spray or tablet or rizatriptan 10 mg at the onset. A few weeks after starting a triptan, he noticed that if he takes any of these triptans 5 minutes before his first drink, he only gets a headache about once a month. He has been taking one of these triptans on a daily basis for 3.5 years. If he does not take the triptan preemptively before drinking, he will get a headache. One hundred percent oxygen at 12 liters per minute was not effective. Topirimate was not effective for prevention. He was prescribed verapamil on a number of occasions but did not start the medication. Despite multiple recommendations, he did not seek counseling for alcohol abuse. The unknown risk of daily triptan use was discussed with the patient several times. Past medical history was otherwise negative. He smokes one pack per day. He has a white-collar job working in sales. Neurological examination is normal. Questions.—How common and what are the triggers in cluster headache? To be considered a trigger, how long after exposure to the trigger should the headache begin? How often is alcohol a trigger and what types? Will greater amounts of alcohol trigger a Case history submitted by: Randolph W. Evans, MD, 1200 Binz no. 1370, Houston, TX 77004, USA.

Interrelationships among the MTHFR 677CT polymorphism (rs1801133), migraine, and cardiovascular disease (CVD) are plausible but remain controversial.Association study among 25,001 white US women, participating in the Women's Health Study, with information on MTHFR 677CT polymorphism. Migraine and migraine aura status were self-reported. Incident CVD events were confirmed after medical record review. We used logistic regression to investigate the genotype-migraine association and proportional hazards models to evaluate the interrelationships of genotype and migraine on incident CVD.At baseline, 4,577 (18.3%) women reported history of migraine; 39.5% of the 3,226 women with active migraine indicated aura. During a mean of 11.9 years of follow-up, 625 CVD events occurred. Carriers of the TT genotype were less likely to have migraine with aura. The multivariable-adjusted relative risk (RR) in the recessive model was 0.79 (95% CI = 0.65-0.96; p = 0.02). The TT genotype did not increase the risk for CVD. In contrast, migraine with aura doubled the risk for CVD (multivariable-adjusted RR = 2.06; 95% CI = 1.53-2.78; p0.0001). Coexistence of migraine with aura and the TT genotype selectively raised this risk (RR = 3.66; 95% CI = 1.69-7.90; p = 0.001). This pattern was driven by a fourfold increased risk for ischemic stroke (multivariable-adjusted RR = 4.19; 95% CI = 1.38-12.74; p = 0.01) and was not apparent for myocardial infarction.Data from this large cohort of women suggest a modest protective effect of the MTHFR 677TT genotype on migraine with aura. The increased risk for cardiovascular disease among migraineurs with aura was magnified for TT genotype carriers, which was driven by a substantially increased risk of ischemic stroke.

Migraine prophylaxis is a stepwise procedure with lifestyle advice followed by consideration of medications. Patients should be advised to try to maintain a regular lifestyle, with regular sleep, meals, exercise, and management of stress, perhaps through relaxation techniques or other ways that are sensible for them. If this regimen does not adequately control their migraines, preventatives are indicated. Patients can choose between evidence-based nutraceuticals such as riboflavin, feverfew, butterbur, or coenzyme Q10, or more traditional pharmaco-therapeutics. Medicine choices are somewhat limited by what is available in each country, but from the full range, the medicines of first choice are beta-adrenoceptor blockers, flunarizine, topiramate, and valproic acid. Beta-adrenoceptor blockers are particularly useful in patients also suffering from hypertension or tachycardia. Following recent studies, topiramate has become a first choice for episodic as well as chronic migraine. It is the only prophylactic drug that may lead to weight loss, but it is sometimes associated with adverse cognitive effects. Valproic acid and flunarizine also have very good prophylactic properties. However, valproic acid is often associated with adverse effects, and flunarizine is unavailable in many countries, including the United States. If sequential monotherapies are ineffective, combinations of first-line drugs should be tried before advancing to drugs of second choice, which are associated with more adverse effects or have less well-established prophylactic properties. Amitriptyline should be used carefully because of its anticholinergic effects, although it is useful in comorbid tension-type headache, depression, and sleep disorders. Methysergide is very effective, but it has been supplanted or even made unavailable in many countries because of its well-described association with retroperitoneal fibrosis. Pizotifen has a slightly better safety profile but is unavailable in the United States. Aspirin is particularly useful in patients needing platelet inhibitors for other medical conditions, but the risk of gastrointestinal bleeding must be considered. The prophylactic properties of magnesium, riboflavin, and coenzyme Q10 are low at best, but their lack of severe adverse effects makes them good treatment options. Magnesium may be particularly useful during pregnancy. Lisinopril and candesartan were shown to be effective in single trials and are preferable in patients with hypertension. Acupuncture may be another alternative; although controlled trials have failed to differentiate its effect from placebo, it is at least innocuous. Botulinum toxin A is not effective in the prophylaxis of episodic migraine.

Background.—The hypocretin receptor 2 (HCRTR2) G1246A polymorphism has been associated with the risk for cluster headache. Since the hypothalamic hypocretin/orexin system projects throughout the nervous system and affects multiple vegetative functions including generation of rhythmicity, vasomotion, autonomic symptoms as well as modulation of nociception, it may also be linked with migraine. Objective.—We thus sought to evaluate whether the HCRTR2 G1246A polymorphism is associated with the risk for migraine. Methods.—We prospectively established a cohort of 146 unrelated patients with migraine. The control group consisted of 279 healthy volunteers. We genotyped patients and controls for the HCRTR2 G1246A polymorphism and examined an association with presence or absence of migraine. Results.—Genotype and allele frequencies were not significantly different between migraine patients and controls (genotype distribution: χ2= 4.13, 2 df, P= .13; allele distribution: χ2= 0.9, 1 df, P= .34). Conclusion.—Our study does not support a major contribution of the HCRTR2 G1246A polymorphism to the pathogenesis of migraine in contrast to its effects in cluster headache.

The risk of cluster headache (CH) is associated with the G-allele of the G1246A polymorphism in the hypocretin receptor 2 ( HCRTR2) gene. First-line medication is effective in only about 70-80% of CH patients. We hypothesized that the HCRTR2 G1246A polymorphism is also of pharmacogenetic relevance in CH and may affect treatment response. We performed a prospective cohort study among 184 unrelated White CH patients. While the HCRTR2 1246G allele was significantly associated with CH in this group, treatment outcomes with triptans, oxygen, verapamil and corticosteroids remained unaffected. Our results do not support a role of the HCRTR2 G1246A polymorphism in drug responses in CH.

Only about 70% of migraine and cluster headache (CH) patients report significant treatment responses to triptans, which are agonists at 5-HT(1B/D) receptors belonging to the family of G protein-coupled receptors. We analyzed whether a common polymorphism in the gene for the G protein beta3 subunit (GNB3 C825T) modulates responder rates to triptans among a cohort of 231 unrelated Caucasian CH patients. A total of 180 CH patients used triptans, of whom 71.1% reported treatment success. The adjusted odds ratio for treatment response to triptans for heterozygous carriers of the GNB3 825T allele was 2.96 (95% confidence interval 1.34-6.56; P=0.0074) vs carriers of the 825CC genotype. The GNB3 genotype status did not affect responses to other acute and preventive therapeutic regimes including oxygen, verapamil, and corticosteroids, i.e., drugs not directly affecting G proteins. We conclude that pain relief by triptans is significantly modulated by a common genetic GNB3 variant.

Migraine is a debilitating neurological disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood. Some debate exists over whether migraine is a disease of vascular dysfunction, or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we performed the largest genetic study of migraine to date, comprising 59,674 cases and 316,078 controls from 22 GWA studies. We identified 45 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 x 10-8) that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X. Furthermore, a subset analysis for migraine without aura (MO) identified seven of the same loci as from the full sample, whereas no loci reached genome-wide significance in the migraine with aura (MA) subset. In subsequent computational analyzes, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

Background While the most accurate diagnosis of migraine typically requires a clinical interview guided by strict diagnostic criteria, an alternative approach that ascertains migraine by questionnaire in population-based settings has been instrumental in the discovery of common genetic variants influencing migraine risk. This result may be surprising. Population-based approaches are often criticized for limited ability to distinguish migraine from other forms of primary headache. It is thus useful to revisit prevailing ideas about population-based ascertainment of migraine to evaluate the extent to which this approach has potential for additional insights into migraine genetics and therefore pathophysiology. Overview We review recent findings suggesting that the success of the population-based approach is derived from the possibility of collecting much larger samples than in the clinic-based setting even at the risk of introducing phenotypic and genetic heterogeneity. The findings are also consistent with new appreciations for the genetic basis of many other common, complex clinical characteristics. However, clinic-based ascertainment and other settings will remain more effective than population-based approaches for investigating certain, often very specific aspects of migraine genetics. Conclusion We argue that the detailed genetic architecture of migraine, various aspects of methodology, and the ultimate sample size achieved by population-based ascertainment will be critical determinants of the future success of this approach to genetic analysis of migraine and its comorbidities.

Objective:To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.Methods:We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.Results:We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 x 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 x 10(-20) for the CE score in MO).Conclusions:Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

Background Migraine is a common comorbidity among individuals with bipolar disorder, but the underlying mechanisms for this co-occurrence are poorly understood. The aim of this study was to investigate the genetic background of bipolar patients with and without migraine. Methods We performed a genome-wide association analysis contrasting 460 bipolar migraneurs with 914 bipolar patients without migraine from the Bipolar Genome Study (BiGS). Results We identified one genome-wide significant association between migraine in bipolar disorder patients and rs1160720, an intronic single nucleotide polymorphism (SNP) in the NBEA gene ( P =2.97×10 −8 , OR: 1.82, 95% CI: 1.47–2.25), although this was not replicated in a smaller sample of 289 migraine cases. Limitations Our study is based on self-reported migraine. Conclusions NBEA encodes neurobeachin, a scaffolding protein primarily expressed in the brain and involved in trafficking of vesicles containing neurotransmitter receptors. This locus has not previously been implicated in migraine per se. We found no evidence of association in data from the GWAS migraine meta-analysis consortium ( n =118,710 participants) suggesting that the association might be specific to migraine co-morbid with bipolar disorder.

Background and Purpose— NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. Methods— Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. Results— The distribution of pathogenic categories varied by study, age, sex, and race ( P Conclusions— This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.

BACKGROUND Fetuin-A, a protein secreted primarily by the liver, has been associated with nonalcoholic fatty liver disease and insulin resistance. In a recent study, higher circulating fetuin-A was associated with cardiovascular events, particularly ischemic stroke. However, these data have not been replicated. METHODS A nested case control design was used to examine the relationship between fetuin-A and ischemic stroke among female participants of the Nurses' Health Study. Fetuin-A was measured in blood samples collected and stored between 1989 and 1990. A total of 459 incident cases of ischemic stroke were identified and confirmed by medical records according to the National Survey of Stroke criteria between 1990 and 2006 and matched to 459 controls by age, race/ethnicity, date of sample collection, menopausal status, postmenopausal hormone use, and smoking status. The association between fetuin-A and ischemic stroke was modeled using conditional logistic regression. RESULTS Circulating fetuin-A was higher in women (P < 0.01) who reported increased body mass index (BMI) of ≥25 kg/m2, total cholesterol ≥200 mg/dL, high-sensitivity C-reactive protein ≥3 mg/L, and current hormone use at baseline. Significant partial Spearman correlations (P < 0.001), adjusted for matching factors, were found between measured concentrations of fetuin-A and triglycerides (r = 0.20), C-reactive protein (r = 0.14), and BMI (r = 0.15). Fetuin-A quartiles were not significantly associated with increased risk of incident ischemic stroke when adjusted for matching factors (relative risk, 1.03; 95% CI, 0.69–1.54, extreme quartiles); additional adjustment for lifestyle factors or cardiovascular disease risk factors and biomarkers did not alter results. CONCLUSIONS In this sample of women, fetuin-A was not significantly associated with risk of ischemic stroke. Further research is needed to explore this association.

Telomere shortening has been implicated in neurodegenerative disorders. However, available data on the association between telomere length and Parkinson's disease (PD) are inconclusive.A nested case-control design was used amongst men participating in the prospective Physicians' Health Study. A large proportion of participants provided blood samples in 1997 and they were followed through 2010. Men with self-reported PD were age-matched to controls in a 1:2 ratio. Quantitative PCR was used to determine the telomere repeat copy number to single gene copy number ratio (TSR) in genomic DNA extracted from peripheral blood leukocytes. TSR was used as a measure for relative telomere length (RTL) in our analyses. Conditional logistic regression was used to determine the risk of PD associated with RTL.Data on RTL were available from 408 cases and 809 controls. Median TSR was shorter in controls than in cases (47.7 vs. 50.2; P = 0.02). The age-adjusted odds ratio (OR) for PD was 0.66 [95% confidence interval (CI) 0.46-0.95; Ptrend over quartiles 0.02] comparing the lowest to the highest quartile. The pattern of association was unchanged when comparing RTL below versus above the median (age-adjusted OR 0.75; 95% CI 0.59-0.96). Associations were similar after additional adjustment for many covariates.Contrary to what was expected, in this large nested case-control study amongst men shorter telomeres were associated with reduced PD risk. Future research on the nature of this counterintuitive association is warranted.