Phenotypic and Molecular Characterisation of Cerebral Amyloid Angiopathy (GENERALITY2)

Phenotypic and Molecular Characterisation of Early-onset Cerebral Amyloid Angiopathy

Cerebral Aβ amyloid angiopathy is a severe disease characterised by amyloid deposits in the cerebral vessels, manifested mainly by recurrent cerebral haematomas and cognitive impairment. Diagnostic criteria are based on brain imaging, but the usefulness of this imaging in predicting the course of the disease remains undetermined. The genetic component is largely understudied. Less than 5% of patients carry mutations or duplications of the APP gene. Susceptibility factors such as APOE genotypes and rare variants recently discovered in Alzheimer's disease within the SORL1, TREM2 or ABCA7, ABCA1 and ATP8B4 genes could play a role in the pathophysiology of cerebral amyloid angiopathy. There is currently no specific treatment available. Based on a national recruitment of patients with cerebral amyloid angiopathy, this project aims to assess the role of genetic variants in the diagnosis and progression of cerebral amyloid angiopathy. A better understanding of the mechanisms, particularly genetic, could help us to develop treatments in the era of gene therapy.

Study Overview

• Status: Recruiting
• Conditions: Cerebral Amyloid Aβ Angiopathy

Detailed Description

This research is carried out on the same blood sample taken during the treatment and sent to the Rouen University Hospital Genetics Laboratory for research into point mutations or duplication of the APP gene as part of the diagnosis of cerebral amyloid angiopathy (CAA). For each gene, the proportions of variant carriers will be compared between cases and controls using a Fisher exact test with R statistical software. To rule out any population stratification bias, the tests will also be carried out using logistic regression adjusted on the first PCA axes (principal component analysis) using the seqmeta function. A Bonferroni correction will then be used to adjust the significance threshold according to the number of genes tested.

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

Contacts and Locations

• Study Contact: Name: David DM MALLET, Director; Phone Number: +33 2 32 88 82 65; Email: Secretariat.DRC@chu-rouen.fr
• Study Contact Backup: Name: Vincent VF FERRANTI, Arc; Phone Number: +33 2 32 88 82 65; Email: vincent.ferranti@chu-rouen.fr

Study Locations

• France
  • Rouen, France, 76031
    • Recruiting
    • University Hospital Rouen
    • Contact: Lou LG GRANGEON, Doctor; Phone Number: +33 02 32 88 37 90; Email: Lou.grangeon@chu-rouen.fr

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Etude proposée aux patients adultes atteints d'angiopathie amyloïde cérébrale pour lesquels un prélèvement sanguin est prévu au titre du diagnostic dans le cadre du soin

Description

Inclusion Criteria:

• Patients with a diagnosis of cerebral amyloid angiopathy (CAA) whose genetic samples are initially sent to the Rouen or Paris-Lariboisière genetics laboratories for molecular diagnosis of a genetic cause, thanks to national recruitment and for whom the patients consent to continuing genetic analyses for research purposes without feedback.
• Diagnosis of cerebral amyloid angiopathy (CAA) certain or probable according to the modified Boston diagnostic criteria (1) (except age)
• Age of onset of symptoms <66 years
• Absence of APP mutation/duplication (analysis must already have been carried out in the laboratory on receipt of the sample as part of routine care)
• Signed consent for research
• Patient covered by a social security scheme

Exclusion Criteria:

• Age at first neurological symptom > 66 years
• Minor patients
• Other differential diagnosis that better explains the clinical situation
• Identification of mutations or duplication of the APP gene
• AAC possible but not probable according to the revised Boston criteria
• Patient deprived of liberty by judicial or administrative decision

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
FREX (French Exome Project) control cohort group; Control cohort corresponding to the FREX cohort (French Exome Project) including 585 exomes of healthy individuals (from 6 French regions) and whose data is already available to research groups for case-control association analysis.
Group of patients with cerebral amyloid angiopathy (CAA); Patients with APOE4 genetic risk factors and rare variants of SORL1, TREM2, ABCA7, ABCA1 and ATP8B4

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
patients with APOE4 genetic risk factors	Define the proportion of patients with APOE4 genetic risk factors (%) in patients with early-onset cerebral amyloid angiopathy (CAA) (<66 years) and patients with causal mutations in the PSEN1 and PSEN2 genes.	1 day
patients with rare variants of SORL1	Define the proportion of patients with rare variants (%) of SORL1, in patients with early-onset cerebral amyloid angiopathy (CAA) (<66 years) and patients with causal mutations in the PSEN1 and PSEN2 genes.	1 day
patients with rare variants of TREM2	Define the proportion of patients with rare variants (%) of TREM2 in patients with early-onset cerebral amyloid angiopathy (CAA) (<66 years) and patients with causal mutations in the PSEN1 and PSEN2 genes.	1 day
patients with rare variants of ABCA7	Define the proportion of patients with rare variants (%) of ABCA7 in patients with early-onset cerebral amyloid angiopathy (CAA) (<66 years) and patients with causal mutations in the PSEN1 and PSEN2 genes.	1 day
patients with rare variants of ABCA1	Define the proportion of patients with rare variants (%) of ABCA1 in patients with early-onset cerebral amyloid angiopathy (CAA) (<66 years) and patients with causal mutations in the PSEN1 and PSEN2 genes.	1 day
patients with rare variants of ATP8B4	Define the proportion of patients with rare variants (%) of ATP8B4 in patients with early-onset cerebral amyloid angiopathy (CAA) (<66 years) and patients with causal mutations in the PSEN1 and PSEN2 genes.	1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genotype/clinical phenotype correlations	Establish genotype/clinical phenotype correlations concerning the age of onset, the severity of the disease and the risk of recurrence of haematomas (identified during follow-up visits at M6 and M12 as part of routine care).	12 months
Biological characterisation of AACs (Aβ42,CSF biomarkers)	- assessment of the diagnostic value of assays for Aβ42 biomarkers currently validated in Alzheimer's disease and related neurocognitive disorders	12 months
Biological characterisation of AACs (Aβ40, CSF biomarkers)	- assessment of the diagnostic value of assays for Aβ40, CSF biomarkers currently validated in Alzheimer's disease and related neurocognitive disorders	12 months
Imaging characterisation of AACs (topography of cerebral bleeds)	- identification of biomarker profiles linked to the topography of cerebral bleeds	12 months
Imaging characterisation of AACs (typology of cerebral bleeds)	- identification of biomarker profiles linked to the typology of cerebral bleeds	12 months
Imaging characterisation of AACs (distribution of cerebral bleeds)	- identification of biomarker profiles linked to the distribution of cerebral bleeds	12 months

Collaborators and Investigators

• Sponsor: University Hospital, Rouen
• Investigators: Principal Investigator: Lou LG GRANGEON, Doctor, University Rouen Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 31, 2023
• Primary Completion (Estimated): July 30, 2027
• Study Completion (Estimated): December 30, 2027

Study Registration Dates

• First Submitted: February 26, 2025
• First Submitted That Met QC Criteria: March 4, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 4, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Phenotypic and molecular characterisation
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Proteostasis Deficiencies; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Intracranial Arterial Diseases; Cerebral Arterial Diseases; Cerebral Small Vessel Diseases; Amyloidosis, Familial; Amyloidosis; Cerebral Amyloid Angiopathy; Cerebral Amyloid Angiopathy, Familial
• Other Study ID Numbers: 2022/0241/OB; 2022-A02248-35 (Other Identifier: French Minister)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The data provided will be the property of the sponsor and will be used solely for its own research activities.

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