Study Results
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Basic Information
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RECRUITING
240 participants
OBSERVATIONAL
2025-11-24
2028-11-30
Brief Summary
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The primary objective is to determine whether genetic variants differ significantly between MA patients with and without PFO. Secondary objectives include assessing cerebral blood flow regulation and platelet function in migraine with aura patients with and without PFO.
Participants will undergo a single study visit including collection of demographic and clinical data and a comprehensive neurosonological assessment. This includes microemboli count, cerebrovascular reactivity tests, and a contrast-enhanced Doppler study for shunt detection. Blood samples will be collected for whole-exome sequencing (focusing on NOTCH3 and an extended gene panel) and for platelet aggregometry.
The study is expected to provide new insights into biological mechanisms linking PFO and MA-potentially involving endothelial dysfunction, altered vascular smooth muscle responses, or platelet activation-thus informing prevention strategies and future research.
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Detailed Description
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The primary objective of the study is to compare the distribution of NOTCH3 gene variants and single nucleotide polymorphisms (SNPs) between MA patients with PFO (PFO+) and MA patients without PFO (PFO-). NOTCH3 encodes a receptor involved in vascular smooth muscle cell differentiation and small-vessel integrity, and pathogenic variants are known to cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Variants in this gene have also been associated with migraine phenotypes and alterations in cerebral small-vessel function. Given the role of Notch signaling pathways in cardiac septation and closure of the fetal foramen ovale, genetic variation in this pathway may contribute to both MA susceptibility and persistence of PFO.
Secondary objectives include: (1) the assessment of variants and SNPs in additional genes involved in Notch signaling, cardiac development, vascular regulation, and PFO heritability; (2) evaluation of the relationship between genetic variants and the degree of right-to-left shunt; (3) comparison of cerebral microembolic signals between PFO+ and PFO- participants using automated transcranial Doppler detection; (4) assessment of cerebrovascular reactivity (CVR) and dynamic cerebral autoregulation (dCA) using standardized neurosonological protocols; and (5) comparison of platelet function profiles between groups.
Each participant undergoes a single study visit. Data collection includes a structured clinical and demographic assessment, detailed characterization of migraine phenotype (including aura characteristics, attack frequency, and coexistence of migraine without aura), and review of available brain magnetic resonance imaging (MRI) findings when present. The neurosonological assessment includes continuous transcranial Doppler monitoring for detection of microembolic signals, evaluation of CVR and cerebral autoregulation using breath-hold and hyperventilation maneuvers with transfer function analysis, and contrast-enhanced right-to-left shunt detection using agitated saline. Peripheral blood samples are collected for genetic analysis and platelet function testing. Whole-exome sequencing is performed, with subsequent analysis focused on a predefined panel of genes, including but not limited to NOTCH3, NOTCH1, JAG1, and HTRA1. Platelet aggregation studies are conducted using standardized laboratory methods.
The planned sample size is 240 participants, equally distributed between the PFO+ and PFO- groups. This sample size is based on the expected prevalence of NOTCH3 SNPs and anticipated differences between groups. Statistical analyses include comparison of allele and genotype frequencies, assessment of Hardy-Weinberg equilibrium, linkage disequilibrium analyses, and multivariable comparisons of neurosonological and platelet function parameters.
By integrating genetic, neurosonological, and hematological data, the PFOCUS study aims to characterize potential biological differences between MA patients with and without PFO and to contribute to a better understanding of migraine-related vascular vulnerability.
Conditions
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Study Design
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CASE_CONTROL
PROSPECTIVE
Study Groups
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Arm 1
Patients with migraine with aura who have a patent foramen ovale (MAPFO+)
Intervention
Neurosonological protocol with continuous Doppler monitoring for microemboli detection, cerebrovascular reactivity and dynamic cerebral autoregulation autoregulation testing, and a contrast-enhanced shunt study using agitated saline; blood samples for whole-exome sequencing and for platelet aggregation study
Arm 2
Patients with migraine with aura without patent foramen ovale (MAPFO-)
Intervention
Neurosonological protocol with continuous Doppler monitoring for microemboli detection, cerebrovascular reactivity and dynamic cerebral autoregulation autoregulation testing, and a contrast-enhanced shunt study using agitated saline; blood samples for whole-exome sequencing and for platelet aggregation study
Interventions
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Intervention
Neurosonological protocol with continuous Doppler monitoring for microemboli detection, cerebrovascular reactivity and dynamic cerebral autoregulation autoregulation testing, and a contrast-enhanced shunt study using agitated saline; blood samples for whole-exome sequencing and for platelet aggregation study
Eligibility Criteria
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Inclusion Criteria
* Age ≥ 18 years
* Both sexes
* Obtained written informed consent to participate in the study
Exclusion Criteria
18 Years
ALL
No
Sponsors
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Azienda Usl di Bologna
OTHER_GOV
Responsible Party
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Principal Investigators
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Matteo Paolucci
Role: PRINCIPAL_INVESTIGATOR
IRCCS Istituto delle Scienze Neurologiche di Bologna
Locations
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IRCCS Istituto delle Scienze Neurologiche di Bologna - AUSL of Bologna
Bologna, BO, Italy
Countries
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Central Contacts
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Facility Contacts
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References
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West BH, Noureddin N, Mamzhi Y, Low CG, Coluzzi AC, Shih EJ, Gevorgyan Fleming R, Saver JL, Liebeskind DS, Charles A, Tobis JM. Frequency of Patent Foramen Ovale and Migraine in Patients With Cryptogenic Stroke. Stroke. 2018 May;49(5):1123-1128. doi: 10.1161/STROKEAHA.117.020160. Epub 2018 Apr 10.
Trabattoni D, Brambilla M, Canzano P, Becchetti A, Teruzzi G, Porro B, Fiorelli S, Muratori M, Tedesco CC, Veglia F, Montorsi P, Bartorelli AL, Tremoli E, Camera M. Migraine in Patients Undergoing PFO Closure: Characterization of a Platelet-Associated Pathophysiological Mechanism: The LEARNER Study. JACC Basic Transl Sci. 2022 Apr 13;7(6):525-540. doi: 10.1016/j.jacbts.2022.02.002. eCollection 2022 Jun.
Takagi H, Umemoto T; ALICE (All-Literature Investigation of Cardiovascular Evidence) Group. A meta-analysis of case-control studies of the association of migraine and patent foramen ovale. J Cardiol. 2016 Jun;67(6):493-503. doi: 10.1016/j.jjcc.2015.09.016. Epub 2015 Oct 31.
Schwaag S, Evers S, Schirmacher A, Stogbauer F, Ringelstein EB, Kuhlenbaumer G. Genetic variants of the NOTCH3 gene in migraine--a mutation analysis and association study. Cephalalgia. 2006 Feb;26(2):158-61. doi: 10.1111/j.1468-2982.2005.01007.x.
Schmidt H, Zeginigg M, Wiltgen M, Freudenberger P, Petrovic K, Cavalieri M, Gider P, Enzinger C, Fornage M, Debette S, Rotter JI, Ikram MA, Launer LJ, Schmidt R; CHARGE consortium Neurology working group. Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease. Brain. 2011 Nov;134(Pt 11):3384-97. doi: 10.1093/brain/awr252. Epub 2011 Oct 17.
Rutten JW, Dauwerse HG, Gravesteijn G, van Belzen MJ, van der Grond J, Polke JM, Bernal-Quiros M, Lesnik Oberstein SA. Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL. Ann Clin Transl Neurol. 2016 Sep 28;3(11):844-853. doi: 10.1002/acn3.344. eCollection 2016 Nov.
Paolucci M, Vincenzi C, Romoli M, Amico G, Ceccherini I, Lattanzi S, Bersano A, Longoni M, Sacco S, Vernieri F, Pascarella R, Valzania F, Zedde M. The Genetic Landscape of Patent Foramen Ovale: A Systematic Review. Genes (Basel). 2021 Dec 6;12(12):1953. doi: 10.3390/genes12121953.
Paolucci M, Altamura C, Vernieri F. The Role of Endothelial Dysfunction in the Pathophysiology and Cerebrovascular Effects of Migraine: A Narrative Review. J Clin Neurol. 2021 Apr;17(2):164-175. doi: 10.3988/jcn.2021.17.2.164.
van Os HJA, Mulder IA, Broersen A, Algra A, van der Schaaf IC, Kappelle LJ, Velthuis BK, Terwindt GM, Schonewille WJ, Visser MC, Ferrari MD, van Walderveen MAA, Wermer MJH; DUST Investigators. Migraine and Cerebrovascular Atherosclerosis in Patients With Ischemic Stroke. Stroke. 2017 Jul;48(7):1973-1975. doi: 10.1161/STROKEAHA.116.016133. Epub 2017 May 19.
Menon S, Cox HC, Kuwahata M, Quinlan S, MacMillan JC, Haupt LM, Lea RA, Griffiths LR. Association of a Notch 3 gene polymorphism with migraine susceptibility. Cephalalgia. 2011 Feb;31(3):264-70. doi: 10.1177/0333102410381143. Epub 2010 Sep 2.
Lipton RB, Scher AI, Kolodner K, Liberman J, Steiner TJ, Stewart WF. Migraine in the United States: epidemiology and patterns of health care use. Neurology. 2002 Mar 26;58(6):885-94. doi: 10.1212/wnl.58.6.885.
Li X, Xie L, Dai J, Zhou X, Chen T, Mao W. A whole-exome sequencing study of patent foramen ovale: investigating genetic variants and their association with cardiovascular disorders. Front Genet. 2024 May 14;15:1405307. doi: 10.3389/fgene.2024.1405307. eCollection 2024.
Lantz M, Sieurin J, Sjolander A, Waldenlind E, Sjostrand C, Wirdefeldt K. Migraine and risk of stroke: a national population-based twin study. Brain. 2017 Oct 1;140(10):2653-2662. doi: 10.1093/brain/awx223.
Kurth T, Chabriat H, Bousser MG. Migraine and stroke: a complex association with clinical implications. Lancet Neurol. 2012 Jan;11(1):92-100. doi: 10.1016/S1474-4422(11)70266-6.
Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018 Jan;38(1):1-211. doi: 10.1177/0333102417738202. No abstract available.
Hu X, Zhou Y, Zhao H, Peng C. Migraine and the risk of stroke: an updated meta-analysis of prospective cohort studies. Neurol Sci. 2017 Jan;38(1):33-40. doi: 10.1007/s10072-016-2746-z. Epub 2016 Oct 26.
Hosseini-Alghaderi S, Baron M. Notch3 in Development, Health and Disease. Biomolecules. 2020 Mar 23;10(3):485. doi: 10.3390/biom10030485.
Guo ZN, Xing Y, Liu J, Wang S, Yan S, Jin H, Yang Y. Compromised dynamic cerebral autoregulation in patients with a right-to-left shunt: a potential mechanism of migraine and cryptogenic stroke. PLoS One. 2014 Aug 14;9(8):e104849. doi: 10.1371/journal.pone.0104849. eCollection 2014.
Dong B, Li Y, Ai F, Geng J, Tang T, Peng W, Tang Y, Wang H, Tian Z, Bu F, Chen L. Genetic variation in patent foramen ovale: a case-control genome-wide association study. Front Genet. 2025 Jan 13;15:1523304. doi: 10.3389/fgene.2024.1523304. eCollection 2024.
Elliott GC, Gurtu R, McCollum C, Newman WG, Wang T. Foramen ovale closure is a process of endothelial-to-mesenchymal transition leading to fibrosis. PLoS One. 2014 Sep 12;9(9):e107175. doi: 10.1371/journal.pone.0107175. eCollection 2014.
Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. Cadasil. Lancet Neurol. 2009 Jul;8(7):643-53. doi: 10.1016/S1474-4422(09)70127-9.
Other Identifiers
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PFOCUS
Identifier Type: -
Identifier Source: org_study_id
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