Genotype, Clinical Features and Imaging of Neuroradiological Abnormalities in CADASIL (GENICa)

The project aims to retrospectively and prospectively analyze a population of CADASIL patients in order to study the natural history of the disease by correlating the symptom spectrum with genetic risk and specific neuroradiological and biological markers

- Stratifying patients according to their disease risk, this could contribute to the discovery of personalized therapeutic targets.

Study Overview

• Status: Recruiting
• Conditions: CADASIL; CADASIL (Diagnosis)

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Anna Bersano, MD; Phone Number: + 39 02.2394; Email: anna.bersano@istituto-besta.it

Study Locations

• Italy
  • Milano, Italy
    • Recruiting
    • Fondazione IRCCS Istituto Neurologico Carlo Besta
    • Contact: Anna Bersano, MD; Phone Number: + 39 02.2394; Email: anna.bersano@istituto-besta.it
• Spain
  • Madrid, Spain
    • Not yet recruiting
    • Hospital Universitario de la Princesa, Madrid
    • Contact: Alicia Gonzales Martinez; Phone Number: 91 520 22 89; Email: alicia.gonzalez.martinez@live.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

All patients diagnosed with genetically confirmed CADASIL and followed in the Cerebrovascular Diseases Outpatient Clinic of Neurology Unit 9 from 2008 to 2023 will be enrolled in the study.

Description

Inclusion criteria:

• patients of either sex older than 18 years of age;
• finding of a pathogenic mutation on genetic analysis of NOTCH3;
• in the absence of unambiguous mutation, presence of characteristic deposits (GOM) within small vessels at skin biopsy

Exclusion criteria:

• do not meet the diagnostic criteria of CADASIL;
• are unable to give consent for the study due to aphasic or cognitive impairment or because they are deceased at the time of enrollment and their next of kin refuse to give consent for study participation.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Deepen the knowledge of the clinical phenotype CADASIL patient	Each patient with CADASIL will undergo to neuroimaging, correlating it with genotype (NOTCH3 gene mutation search outcome), clinical (e.g., the index event, cerebrovascular risk factors, associated manifestations) and instrumental (radiological) characterization.	T0- T1 (24 months)
Identify potentially reversible risk factors for disease progression	At baseline, each patient will undergo collection of demographic and clinical data (e.g., the index event, cerebrovascular risk factors, associated manifestations). Disability will be assessed with the modified Rankin Scale (mRS). Neuropsychological assessment will include administration of the Montreal Cognitive Assesment (MoCA) as a screening test. Some components of executive functions will be assessed by Frontal Assesment Battery (F.A.B) scale as a screening test of executive functions, Trail Making Test (TMT) A and B to assess visual search, psychomotor speed and selective attention (TMT test A) and in addition divided and alternating attention and cognitive flexibility by TMT test B, Attentional Matrices to assess sustained attention and visual search and Modified Five Point Test to assess spatial fluency. Finally by means of the Forward Word Span and Backward Digit Span, Verbal Short-Term Memory and Working Memory will be assessed. Alongside the neuropsychological assessment of	0-24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identify clinical, genetic, biological and neuroradiological markers	Patients will undergo an MRI study with high-field (3T) equipment consisting of standard morphologic sequences (T1 3D TSE, T2 TSE, 3D FLAIR, SWI, DWI) to assess the extent of leukoencephalopathy, its distribution pattern, the presence of gaps and/or recent ischemic lesions in DWI sequences, perivascular spaces, and concomitant microhemorrhages. Laboratory approaches aimed at differentiating progenitors of specific cell populations (e.g., endothelial and vascular smooth muscle cells) from peripheral blood mononuclear cells (PBMCs) or fibroblasts from skin will be performed. In addition, it will be possible to isolate from peripheral blood the plasma component, intended for research and characterization of potential circulating biomarkers, by appropriate multi-omics approaches (transcriptomics, proteomics, lipidomics).	0-30 months
Deepen knowledge of the neuroradiological phenotype of CADASIL patients, depending on the NOTCH3 mutation locus identified (high, moderate or low risk)	Patients will undergo an MRI study with high-field (3T), in particular, high-resolution volumetric FLAIR sequences will be used to allow subsequent segmentation analyses of vascular lesions and a more correct quantitative assessment of cortical thickness values of brain areas. Advanced imaging sequences, particularly epi bold resting state for the study of functional brain connectivity, will also be provided.	0-30 months

Collaborators and Investigators

• Sponsor: Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta

Publications and helpful links

General Publications

• 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.
• Ruchoux MM, Maurage CA. CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neuropathol Exp Neurol. 1997 Sep;56(9):947-64.
• Rutten JW, Van Eijsden BJ, Duering M, Jouvent E, Opherk C, Pantoni L, Federico A, Dichgans M, Markus HS, Chabriat H, Lesnik Oberstein SAJ. The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1-6 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7-34 pathogenic variant. Genet Med. 2019 Mar;21(3):676-682. doi: 10.1038/s41436-018-0088-3. Epub 2018 Jul 22. Erratum In: Genet Med. 2019 Aug;21(8):1895. doi: 10.1038/s41436-018-0306-z.
• Opherk C, Peters N, Herzog J, Luedtke R, Dichgans M. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004 Nov;127(Pt 11):2533-9. doi: 10.1093/brain/awh282. Epub 2004 Sep 13.

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2023
• Primary Completion (Estimated): April 30, 2027
• Study Completion (Estimated): October 31, 2027

Study Registration Dates

• First Submitted: April 3, 2025
• First Submitted That Met QC Criteria: April 14, 2025
• First Posted (Actual): April 22, 2025

Study Record Updates

• Last Update Posted (Actual): April 22, 2025
• Last Update Submitted That Met QC Criteria: April 14, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: CADASIL; NOTCH3
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Mental Disorders; Pathologic Processes; Genetic Diseases, Inborn; Neurocognitive Disorders; Brain Infarction; Brain Ischemia; Infarction; Necrosis; Dementia; Ischemia; Intracranial Arterial Diseases; Stroke; Cerebral Arterial Diseases; Cerebral Infarction; Cerebral Small Vessel Diseases; Dementia, Vascular; CADASIL; Dementia, Multi-Infarct
• Other Study ID Numbers: GENICa

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No