Tobias Freilinger

University of Tuebingen, Tübingen, Baden-Württemberg, Germany

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Publications (61)368.86 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Before the genome-wide association (GWA) era, many hypothesis-driven candidate gene association studies were performed that tested whether DNA variants in genes that had been selected based on prior knowledge about migraine pathophysiology were associated with migraine. Most studies involved small sample sets without robust replication, thereby making the risk of false-positive findings high. Genome-wide marker data of thousands of migraine patients and controls from the International Headache Genetics Consortium provide a unique opportunity to re-evaluate key findings from candidate gene association studies (and other non-GWA genetic studies) in a much larger data set. We selected 21 genes from published candidate gene association studies and six additional genes from other non-GWA genetic studies in migraine. Single nucleotide polymorphisms (SNPs) in these genes, as well as in the regions 500 kb up- and downstream, were inspected in IHGC GWAS data from 5175 clinic-based migraine patients with and without aura and 13,972 controls. None of the SNPs in or near the 27 genes, including the SNPs that were previously found to be associated with migraine, reached the Bonferroni-corrected significance threshold; neither when analyzing all migraine patients together, nor when analyzing the migraine with and without aura patients or males and females separately. The available migraine GWAS data provide no clear evidence for involvement of the previously reported most promising candidate genes in migraine. © International Headache Society 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
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    ABSTRACT: BACKGROUND: The purpose of this prospective study was to perform a head-to-head comparison of the two methods most frequently used for evaluation of carotid plaque characteristics: Multi-detector Computed Tomography Angiography (MDCTA) and black-blood 3 T-cardiovascular magnetic resonance (bb-CMR) with respect to their ability to identify symptomatic carotid plaques. METHODS: 22 stroke unit patients with unilateral symptomatic carotid disease and >50% stenosis by duplex ultrasound underwent MDCTA and bb-CMR (TOF, pre- and post-contrast fsT1w-, and fsT2w- sequences) within 15 days of symptom onset. Both symptomatic and contralateral asymptomatic sides were evaluated. By bb-CMR, plaque morphology, composition and prevalence of complicated AHA type VI lesions (AHA-LT6) were evaluated. By MDCTA, plaque type (non-calcified, mixed, calcified), plaque density in HU and presence of ulceration and/or thrombus were evaluated. Sensitivity (SE), specificity (SP), positive and negative predictive value (PPV, NPV) were calculated using a 2-by-2-table. RESULTS: To distinguish between symptomatic and asymptomatic plaques AHA-LT6 was the best CMR variable and presence / absence of plaque ulceration was the best CT variable, resulting in a SE, SP, PPV and NPV of 80%, 80%, 80% and 80% for AHA-LT6 as assessed by bb-CMR and 40%, 95%, 89% and 61% for plaque ulceration as assessed by MDCTA. The combined SE, SP, PPV and NPV of bb-CMR and MDCTA was 85%, 75%, 77% and 83%, respectively. CONCLUSIONS: Bb-CMR is superior to MDCTA at identifying symptomatic carotid plaques, while MDCTA offers high specificity at the cost of low sensitivity. Results were only slightly improved over bb-CMR alone when combining both techniques.
    Journal of Cardiovascular Magnetic Resonance 10/2014; 16(1):84. DOI:10.1186/s12968-014-0084-y
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    ABSTRACT: There has been intensive debate whether migraine with aura (MA) and migraine without aura (MO) should be considered distinct subtypes or part of the same disease spectrum. There is also discussion to what extent migraine cases collected in specialised headache clinics differ from cases from population cohorts, and how female cases differ from male cases with respect to their migraine. To assess the genetic overlap between these migraine subgroups, we examined genome-wide association (GWA) results from analysis of 23,285 migraine cases and 95,425 population-matched controls.
    Cephalalgia 09/2014; DOI:10.1177/0333102414547784
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    ABSTRACT: Migraine has an important genetic component. The prototypic monogenic form of migraine is hemiplegic migraine, a rare subtype of migraine with aura, for which three causative genes have been identified. Studies of transgenic animal models have substantially improved our understanding of the molecular pathophysiology of this monogenic model disease as well as of migraine in general. Beyond this, there are other (rarer) monogenic forms of migraine, e.g., in the context of hereditary mostly vascular syndromes such as CADASIL. By contrast, the common types of migraine with and without aura are genetically complex. With the identification of the first robust genetic risk variants in large genome-wide association studies, our knowledge in this still dynamically expanding field has substantially increased. This review summarizes the current status of migraine genetics, with a special focus on hemiplegic migraine as well as the most recent findings in complex migraine genetics. In addition, the first preliminary findings on the genetics of other types of primary headache disorders (cluster headache, tension-type headache) are briefly reviewed.
    Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 07/2014; 57(8). DOI:10.1007/s00103-014-1998-0
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    ABSTRACT: Familial hemiplegic migraine (FHM) is a rare subtype of migraine with transient hemiplegic aura. We describe three unrelated families with familial hemiplegic migraine type II (FHM2). Retrospectively, information on 47 family members could be obtained, 15 by personal examination and 32 by indirect anamnesis from relatives. Genetic analyses were performed in 13 patients. One family had a novel missense mutation in the ATP1A2 gene (c.659C>T, p.Ser220Leu) that segregated with the phenotype in three generations. Two further unrelated families with different ethnic backgrounds (one from Germany and one from Russia) had a missense mutation that has not been described as yet in FHM, but occurred in only a single patient with sporadic hemiplegic migraine (c.2723G>A, p.Arg908Gln). Clinically the patients had severe attacks lasting up to several weeks as well as epileptic seizures. Three patients with a proven mutation in the ATP1A2 gene clinically presented without hemiparesis. Furthermore, there was a possible relation of FHM2 to mental retardation in another two patients. Clinical symptoms may last for several weeks in some patients. Patients with FHM2 may also present without hemiplegia. Therefore, the full family history has to be taken into account to establish the diagnosis of FHM.
    Cephalalgia 10/2013; 34(3). DOI:10.1177/0333102413506128
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    ABSTRACT: Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P < 5 x 10(-8)). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.
    Nature Genetics 08/2013; 45(8):912-7. DOI:10.1038/ng.2676
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    ABSTRACT: Background To determine if black-blood 3 T cardiovascular magnetic resonance (bb-CMR) can depict differences between symptomatic and asymptomatic carotid atherosclerotic plaques in acute ischemic stroke patients. Methods In this prospective monocentric observational study 34 patients (24 males; 70 ±9.3 years) with symptomatic carotid disease defined as ischemic brain lesions in one internal carotid artery territory on diffusion weighted images underwent a carotid bb-CMR at 3 T with fat-saturated pre- and post-contrast T1w-, PDw-, T2w- and TOF images using surface coils and Parallel Imaging techniques (PAT factor = 2) within 10 days after symptom onset. All patients underwent extensive clinical workup (lab, brain MR, duplex sonography, 24-hour ECG, transesophageal echocardiography) to exclude other causes of ischemic stroke. Prevalence of American Heart Association lesion type VI (AHA-LT6), status of the fibrous cap, presence of hemorrhage/thrombus and area measurements of calcification, necrotic core and hemorrhage were determined in both carotid arteries in consensus by two reviewers who were blinded to clinical information. McNemar and Wilcoxon's signed rank tests were use for statistical comparison. A p-value <0.05 was considered statistically significant. Results Symptomatic plaques showed a higher prevalence of AHA-LT6 (67.7% vs. 11.8%; p < 0.001; odds ratio = 12.5), ruptured fibrous caps (44.1% vs. 2.9%; p < 0.001; odds ratio = 15.0), juxtaluminal thrombus (26.5 vs. 0%; p < 0.01; odds ratio = 7.3) and intraplaque hemorrhage (58.6% vs. 11.8%; p = 0.01; odds ratio = 3.8). Necrotic core and hemorrhage areas were greater in symptomatic plaques (14.1 mm2 vs. 5.5 mm2 and 13.6 mm2 vs. 5.3 mm2; p < 0.01, respectively). Conclusion 3 T bb-CMR is able to differentiate between symptomatic and asymptomatic carotid plaques, demonstrating the potential of bb-CMR to differentiate between stable and vulnerable lesions and ultimately to identify patients with low versus high risk for cardiovascular complications. Best predictors of the symptomatic side were a ruptured fibrous cap, AHA-LT 6, juxtaluminal hemorrhage/thrombus, and intraplaque hemorrhage.
    Journal of Cardiovascular Magnetic Resonance 05/2013; 15(1):44. DOI:10.1186/1532-429X-15-44
  • Neurology 11/2012; 79(19):2008-9. DOI:10.1212/WNL.0b013e3182735c68
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    ABSTRACT: Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10(-5) for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10(-4); combined P = 7.06 × 10(-11)) and at 3p24 (near TGFBR2; replication P = 1.0 × 10(-4); combined P = 1.17 × 10(-9)). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10(-8) and P = 0.02; combined P = 3.86 × 10(-8), respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.
    Nature Genetics 06/2012; 44(7):777-82. DOI:10.1038/ng.2307
  • RöFo - Fortschritte auf dem Gebiet der R 05/2012; 184(S 01). DOI:10.1055/s-0032-1311227
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    ABSTRACT: Our goal was to assess the prevalence of complicated American Heart Association (AHA) lesion type VI plaques in the carotid arteries of patients with cryptogenic stroke. In up to 40% of ischemic stroke patients, no definite cause can be established despite extensive workup (i.e., cryptogenic stroke). To test the hypothesis if nonstenosing complicated carotid plaques may be the underlying etiology in some of these patients, we used high-resolution black-blood carotid magnetic resonance imaging (MRI), which can quantitatively assess plaque composition and morphology with good correlation to histopathology. Specifically, we focused on AHA type VI plaques, which are characterized by hemorrhage, thrombus, or fibrous cap rupture. Thirty-two consecutive patients (22 male; mean age 71.7 ± 11.9 years) with cryptogenic stroke and nonstenosing (<50%) eccentric carotid plaques were recruited from a single stroke unit. All patients underwent extensive clinical workup (brain MRI, duplex sonography, electrocardiography and Holter monitoring, transthoracic and transesophageal echocardiography, and laboratory investigations) to exclude other causes of stroke. All patients received a black-blood carotid MRI at 3-T with fat-saturated pre- and post-contrast T-1-, proton density-, and T-2-weighted and time-of-flight images using surface coils and parallel imaging techniques. Prevalence of AHA type VI plaque was determined in both carotid arteries on the basis of previously published MRI criteria. AHA type VI plaques were found in 12 of 32 arteries (37.5%) ipsilateral to the stroke, whereas there were no AHA type VI plaques contralateral to the stroke (p = 0.001). The most common diagnostic feature of AHA type VI plaques was intraplaque hemorrhage (75%), followed by fibrous plaque rupture (50%) and luminal thrombus (33%). This pilot study suggests that arterio-arterial embolism from complicated, nonstenosing carotid atherosclerotic plaques may play a role in a subgroup of patients previously diagnosed with cryptogenic stroke. To further evaluate the significance of AHA type VI plaques in cryptogenic stroke, future studies will have to analyze both clinical and imaging follow-up data, including event rates for secondary strokes.
    JACC. Cardiovascular imaging 04/2012; 5(4):397-405. DOI:10.1016/j.jcmg.2012.01.012
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    ABSTRACT: PURPOSE To determine if high-resolution 3T magnetic resonance imaging (hr-MRI) can depict differences between symptomatic and asymptomatic carotid atherosclerotic plaques. METHOD AND MATERIALS In this prospective monocentric observational study 34 patients (7 females; 70±9.3 years) with acute symptomatic carotid disease defined as ischemic brain lesions in one carotid artery territory on diffusion weighted images underwent a carotid black-blood hr-MRI at 3.0-Tesla with fat-saturated pre- and post-contrast T1w-, PDw-, T2w- and TOF images using surface coils and Parallel Imaging techniques (PAT factor=2) within 7 days after symptom onset. All patients underwent extensive clinical workup (lab, brain MRI, duplex sonography, 24-hour ECG, transoesophageal echocardiography) to exclude other causes of ischemic stroke. Prevalence of American Heart Association lesion type VI (AHA-LT6) and thrombus, status of the fibrous cap, presence and type of hemorrhage were qualitatively and quantitatively determined in both carotid arteries based on previously published MRI criteria by two reviewers in consensus who were blinded to the clinical information. The Mc Nemar Test was used for statistical comparison. A p-value <0.05 was considered statistically significant. RESULTS Symptomatic plaques, compared to asymptomatic plaques, had a higher prevalence of AHA-LT6 (65.5% vs. 10.3%; P<0.001), ruptured/ulcerated fibrous caps (34.5% vs. 3.5%; P=0.012), plaque hemorrhage (58.6% vs. 10.3%; P=0.001), early subacute hemorrhage (27.6% vs. 0%; P=0.008) and juxtaluminal thrombus (10.3% vs. 0%; p=n.s.). Quantitatively, maximum necrotic core and hemorrhage area were greater in symptomatic than in asymptomaitc plaques (13.6 mm² vs. 5.5 mm² and 8.0 mm² vs. 1.3 mm² with p<0.01), while mean vessel and lumen areas did not significantly differ between both groups. CONCLUSION 3T hr-MRI is able to differentiate between symptomatic and asymptomatic carotid plaques, demonstrating the high potential of hr-MRI to differentiate between stable and vulnerable lesions and ultimately to identify patients with low versus high risk for cardiovascular complications. CLINICAL RELEVANCE/APPLICATION 3T hr-MRI is a potent tool in the differentiation between stable and vulnerable lesions and can ultimately help identify patients who are likely to benefit from interventional or surgical therapy.
    Radiological Society of North America 2011 Scientific Assembly and Annual Meeting; 11/2011
  • T Freilinger, T Saam, M Duering, M Dichgans, N Peters
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    ABSTRACT: Cervical artery dissection (CAD) is an important etiology of stroke in young adults. Its etiology is incompletely understood. Here, we report a young woman who presented with acute ischemic stroke in the setting of internal carotid artery (ICA) dissection and essential thrombocythemia (ET). We present a review of previous cases with comorbidity of CAD and ET and discuss the pathophysiological implications of this co-occurrence. In particular, we speculate that ET may increase the susceptibility of cervical vessels to spontaneous dissection, for example, by disturbing the microcirculation within the vessel wall.
    Clinical and Applied Thrombosis/Hemostasis 11/2011; 17(6):E138-40. DOI:10.1177/1076029610391651
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    ABSTRACT: The therapeutic effects of 4-aminopyridine (4AP) were investigated in a randomized, double-blind, crossover trial in 10 subjects with familial episodic ataxia with nystagmus. After randomization, placebo or 4AP (5 mg 3 times daily) was administered for 2 3-month-long treatment periods separated by a 1-month-long washout period. The primary outcome measure was the number of ataxia attacks per month; the secondary outcome measures were the attack duration and patient-reported quality of life (Vestibular Disorders Activities of Daily Living Scale [VDADL]). Nonparametric tests and a random-effects model were used for statistical analysis. The diagnosis of episodic ataxia type 2 (EA2) was genetically confirmed in 7 subjects. Patients receiving placebo had a median monthly attack frequency of 6.50, whereas patients taking 4AP had a frequency of 1.65 (p = 0.03). Median monthly attack duration decreased from 13.65 hours with placebo to 4.45 hours with 4AP (p = 0.08). The VDADL score decreased from 6.00 to 1.50 (p = 0.02). 4AP was well-tolerated. This controlled trial on EA2 and familial episodic ataxia with nystagmus demonstrated that 4AP decreases attack frequency and improves quality of life. Level of evidence: This crossover study provides Class II evidence that 4AP decreases attack frequency and improves the patient-reported quality of life in patients with episodic ataxia and related familial ataxias.
    Neurology 07/2011; 77(3):269-75. DOI:10.1212/WNL.0b013e318225ab07
  • RöFo - Fortschritte auf dem Gebiet der R 04/2011; 183(S 01). DOI:10.1055/s-0031-1279364
  • Neurology 01/2011; 76(3):305-6. DOI:10.1212/WNL.0b013e3182074be8
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    ABSTRACT: Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.
    Nature Genetics 01/2011; 43(7):695-8. DOI:10.1038/ng.856
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    ABSTRACT: PURPOSE Although distinct pathogenetic mechanisms for ischemic stroke have long been recognized, a definite or even probable etiology can not be established in about one third of all patients (“cryptogenic strokes”). Recent studies have shown that high-resolution carotid MRI is able to identify complicated American Heart Association lesion type VI (AHA-LT6) with hemorrhage, thrombus or rupture of the fibrous cap with good correlation to histopathology. The purpose of our study was to evaluate the prevalence of AHA-LT6 in carotid arteries of subjects with cryptogenic stroke. METHOD AND MATERIALS 30 consecutive patients (24 men, mean age 69.9 ± 11.9 years) with cryptogenic stroke and intimal thickening by duplex sonography were recruited from our stroke unit. All patients underwent extensive clinical workup (lab, brain MRI, duplex sonography, 24-hour ECG, transesophageal echocardiography) to exclude carotid stenosis ≥ 50%, cardiac embolism, small vessel disease and other causes of stroke. All subjects received a high-resolution carotid black-blood MRI at 3.0-Tesla with fat-saturated pre- and post-contrast T1w-, PDw-, T2w- and TOF images using surface coils and Parallel Imaging techniques (PAT factor=2). Prevalence of AHA-LT6 was determined in both carotid arteries based on previously published MRI criteria by two experienced reviewers who were blinded to the clinical information. RESULTS AHA-LT6 with hemorrhage, rupture of the fibrous cap and / or thrombus were found in 14 out of 30 arteries (46.7%) ipsilateral and in 1 out of 30 arteries (3.3%) contralateral to the ischemic, “cryptogenic” stroke (P<0.001). Of the 15 plaques classified as AHA-LT6, 13 had plaque hemorrhage, 2 had mural thrombi and 8 a rupture of the fibrous cap. CONCLUSION Complicated non-stenotic carotid atherosclerotic lesions were found significantly more often ipsilateral than contralateral to ischemic “cryptogenic” stroke. CLINICAL RELEVANCE/APPLICATION This study suggest that arterio-arterial embolism from non-stenotic carotid plaques play a role in the pathogenesis in a subset of subjects previously diagnosed with a cryptogenic stroke.
    Journal of Cardiovascular Magnetic Resonance 01/2011; DOI:10.1186/1532-429X-13-S1-P379
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    ABSTRACT: Hemiplegic migraine (HM) is a rare and severe subtype of migraine with aura, characterized by some degree of hemiparesis and other aura symptoms. Mutations in three genes (CACNA1A, ATP1A2 and SCN1A) have been detected in familial and, more rarely, in sporadic cases. The disease can be complicated by permanent neurological deficits, the most frequent one being a cerebellar syndrome; in addition, mental retardation has been recognized as part of the phenotypic spectrum. Here, we report a Caucasian male with a novel CACNA1A mutation and an unusual clinical phenotype: the patient, who had had a history of only two HM attacks, sought medical advice at age 49 primarily because of increasing cognitive decline accompanied by cerebellar dysfunction. While common neurodegenerative causes were excluded, neuropsychological evaluation revealed a distinct profile of deficits of a subcortico-prefrontal type as previously reported in patients with cerebellar dysfunction. This suggests a possible causal link between cerebellar and cognitive disturbances in this patient; in addition to these pathophysiological aspects, we review of the role of the cerebellum in cognition.
    Journal of the neurological sciences 10/2010; 300(1-2):160-3. DOI:10.1016/j.jns.2010.09.032

Publication Stats

1k Citations
368.86 Total Impact Points

Institutions

  • 2014–2015
    • University of Tuebingen
      • Hertie Institute for Clinical Brain Research
      Tübingen, Baden-Württemberg, Germany
  • 2005–2014
    • Ludwig-Maximilians-University of Munich
      • • Department of Neurology
      • • Department of Urology
      München, Bavaria, Germany
  • 2012
    • Munich Re
      München, Bavaria, Germany
    • University Hospital München
      München, Bavaria, Germany
  • 2009
    • Technische Universität München
      München, Bavaria, Germany
  • 2008
    • Technische Universität Berlin
      • Department of Chemistry
      Berlin, Land Berlin, Germany
    • Leiden University Medical Centre
      • Department of Neurology
      Leyden, South Holland, Netherlands
  • 2004
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany