Neurogenetic And Hemodynamic Of Migraine Aura And Pfo

NCT07349004 | Recruiting

• 1 other identifier: PFOCUS
• Study Type: observational
• Target: 240
• Locations: 1 country
• Sites: 1

Brief Summary

The PFOCUS Study aims to clarify the relationship between patent foramen ovale (PFO) and migraine with aura (MA). Patients diagnosed with MA according to ICHD-3 criteria will be classified as cases (PFO+) or controls (PFO-) based on the presence or absence of a right-to-left shunt detected by transcranial Doppler or a previously documented PFO. The study will enroll 240 adult participants over 36 months. The primary objective is to determine whether genetic variants differ significantly between patients with MA with and without PFO. Secondary objectives include assessing cerebral blood flow regulation and platelet function in patients with MA with and without PFO. Participants will undergo a single study visit including the collection of demographic and clinical data and a comprehensive neurosonological assessment. This will include microembolic signal counts, cerebrovascular reactivity testing, and a contrast-enhanced transcranial Doppler study for shunt detection. Blood samples will be collected for whole-exome sequencing (with a focus on NOTCH3 and an expanded gene panel) and for platelet aggregometry. The study is expected to provide new insights into the biological mechanisms linking PFO and MA-potentially involving endothelial dysfunction, altered vascular smooth muscle responses, or platelet activation-thereby informing prevention strategies and guiding future research.

Conditions

Migraine With Aura

Keywords

patent foramen ovale; migraine with aura; CADASIL

Outcome Measures

Primary Outcomes (1)

• Comparison of number of NOTCH3 genetic variants

  To evaluate whether significant differences exist in the frequency of NOTCH3 genetic variants between patients with migraine with aura who have a patent foramen ovale (PFO+) and those without (PFO-). Min=0, max undefined.

  T0 (day 1)

Secondary Outcomes (5)

• Comparison of number of genetic variants in other selected genes

  T0 (day 1)

• Correlation of genetic variants with shunt size

  T0 (day 1)

• Comparison in number of spontaneous microeboli

  T0 (day 1)

• Comparison in cerebrovascular reactivity between PFO+ and PFO- patients

  T0 (day 1)

• Differences in platelet function profiles between PFO+ and PFO- patients

  T0 (day 1)

Study Arms (2)

Arm 1

Patients with migraine with aura who have a patent foramen ovale (MAPFO+)

Other: Intervention

Arm 2

Patients with migraine with aura without patent foramen ovale (MAPFO-)

Other: Intervention

Interventions

Intervention OTHER

Neurosonological protocol with continuous Doppler monitoring for microemboli detection, cerebrovascular reactivity and dynamic cerebral autoregulation testing, and a contrast-enhanced shunt study using agitated saline; blood samples for whole-exome sequencing and platelet aggregation studies.

Arm 1; Arm 2

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

primary care clinic

You may qualify if:

• Diagnosis of migraine with aura (according to Chapter 1.2 of the International Classification of Headache Disorders, 3rd edition \[ICHD-3\])
• Age ≥ 18 years
• Both sexes
• Obtained written informed consent to participate in the study

You may not qualify if:

• History of congenital heart disease

Sponsors & Collaborators

• Azienda Usl di Bologna: lead

Study Sites (1)

IRCCS Istituto delle Scienze Neurologiche di Bologna - AUSL of Bologna

Bologna, BO, 40139, Italy

RECRUITING

Related Publications (21)

• 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.

  PMID: 29636424 BACKGROUND

• 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.

  PMID: 35818509 BACKGROUND

• 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.

  PMID: 26527111 BACKGROUND

• 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.

  PMID: 16426270 BACKGROUND

• 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.

  PMID: 22006983 BACKGROUND

• 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.

  PMID: 27844030 BACKGROUND

• 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.

  PMID: 34946902 BACKGROUND

• 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.

  PMID: 33835736 BACKGROUND

• 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.

  PMID: 28526767 BACKGROUND

• 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.

  PMID: 20813781 BACKGROUND

• 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.

  PMID: 11914403 BACKGROUND

• 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.

  PMID: 38808331 BACKGROUND

• 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.

  PMID: 28969391 BACKGROUND

• 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.

  PMID: 22172624 BACKGROUND

• 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.

  PMID: 29368949 BACKGROUND

• 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.

  PMID: 27785579 BACKGROUND

• Hosseini-Alghaderi S, Baron M. Notch3 in Development, Health and Disease. Biomolecules. 2020 Mar 23;10(3):485. doi: 10.3390/biom10030485.

  PMID: 32210034 BACKGROUND

• 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.

  PMID: 25121485 BACKGROUND

• 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.

  PMID: 39872005 BACKGROUND

• 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.

  PMID: 25215881 BACKGROUND

• 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.

  PMID: 19539236 BACKGROUND

MeSH Terms

Conditions

Migraine with Aura; Foramen Ovale, Patent; CADASIL

Interventions

Methods

Condition Hierarchy (Ancestors)

Migraine Disorders; Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Heart Septal Defects, Atrial; Heart Septal Defects; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cerebral Infarction; Brain Infarction; Brain Ischemia; Cerebrovascular Disorders; Cerebral Small Vessel Diseases; Dementia, Vascular; Cerebral Arterial Diseases; Intracranial Arterial Diseases; Stroke; Dementia; Vascular Diseases; Genetic Diseases, Inborn; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis

Intervention Hierarchy (Ancestors)

Investigative Techniques

Study Officials

• Matteo Paolucci

  IRCCS Istituto delle Scienze Neurologiche di Bologna

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Matteo Paolucci

CONTACT

+390513172087; matteo.paolucci@ausl.bologna.it

Andrea Zini

CONTACT

+390516478810; a.zini@ausl.bologna.it

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2026
• First Posted: January 16, 2026
• Study Start: November 24, 2025
• Primary Completion: November 24, 2025
• Study Completion (Estimated): November 1, 2028
• Last Updated: February 11, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)