The Fingerprinting of Inherited Leukoencephalopathies: A New Brain Imaging, Genetic and Clinical Assessment

Leukoencephalopathies Clinical Trial

— FIABA  

Official title:

The Fingerprinting of Inherited Leukoencephalopathies: A New Brain Imaging, Genetic and Clinical Assessment (FIABA)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06332625
• Other study ID #: PNRR-MR1-2022-12375648
• Status: Recruiting
• Start date: May 22, 2023
• Est. completion date: November 22, 2025

Study information

• Verified date: March 2024
• Source: IRCCS Fondazione Stella Maris
• Contact: Roberta Battini
• Phone: 050886282
• Email: rbattini[@]fsm.unipi.it
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

Inherited leukoencephalopathies are a broad spectrum of genetically determined disorders, characterized by specific involvement of the white matter of the central nervous system. These pathologies are almost as common as other acquired white matter disorders, such as acute disseminated encephalomyelitis and multiple sclerosis. The onset can occur at any age, from prenatal life to adulthood, and the clinical picture is mostly progressive, but can also be non-evolving or, rarely, improve over time. Thanks to new diagnostic approaches, including next-generation genetic sequencing and recognition of magnetic resonance imaging patterns, in recent years the investigators have witnessed a significant increase in the number of genetically defined leukoencephalopathies. However, despite advances in genetic studies, inherited leukoencephalopathies include a large number of inherited white matter diseases in children and adults and remain of unknown cause in many patients (about 40%). This significant percentage of cases of unknown etiology represents a major challenge for public health, both in prognostic terms and, consequently, economically. However, even in leukoencephalopathies of genetically determined cause, the absence of specific biomarkers can be a limiting factor in the design and execution of clinical studies in search of promising therapies. As in other fields of neurology, the integration of clinical and genetic data with brain MRI data plays a fundamental role in the diagnostics of subjects affected by these pathologies. Currently, the methodologies commonly used in magnetic resonance imaging are qualitative, and evaluate brain lesions through the contrast between white and gray matter. The lack of specific biomarkers is therefore a limiting factor in the design of therapeutic challenges. In this regard, the development of new multiparametric quantitative magnetic resonance imaging (qMRI) methods could allow the investigators to identify new biomarkers to assess the etiology behind leukodystrophies, increasing diagnostic power and understanding the progression or improvement of leukoencephalopathy for both future trials and existing therapies. In this perspective, recent rapid "transient-state" magnetic resonance imaging methods, such as MR Fingerprinting (MRF), have proven effective in efficiently separating different components of brain tissue. These techniques consist of rapid and highly undersampled acquisitions performed by continuously changing the MR sequence parameters, thus obtaining a signal evolution that is unique for each combination of underlying tissue properties. Furthermore, if these techniques have already shown their validity at 3 Tesla, they could be even more informative in 7T MRI where the use of qMRI could provide more details thanks to the high image resolution.

The project's objective is to evaluate and validate new and innovative quantitative magnetic resonance imaging (qMRI) methodologies at both clinical and ultra-high fields in inherited leukodystrophies and those of unknown etiology.

This is a national, multi-institutional, multicenter exploratory study on the potential identification and predictability of early structural and metabolic markers in quantitative MRI at 3T and 7T in the diagnosis and follow-up of leukodystrophy and leukoencephalopathy in adults and during development.

The study will include multiple sub-studies:

1. A cross-sectional study in leukoencephalopathies at clinical fields.

2. A longitudinal study in leukoencephalopathies at 3T: natural history and therapy outcomes.

3. A cross-sectional and longitudinal study at 7T: The added value of ultra-high-field Magnetic Resonance Imaging in leukoencephalopathies.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: November 22, 2025
• Est. primary completion date: February 5, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 0 Years to 30 Years

Eligibility

Inclusion Criteria:

• For MRI examinations at clinical fields:

• Patients under 30 years of age with leukoencephalopathy already diagnosed and listed in institutional clinical databases or arriving at any Operational Unit during the project that meet the standard inclusion criteria;

• Typical development patients under 30 years of age undergoing brain MRI for clinical reasons other than leukoencephalopathy (e.g., headache) with normal brain MRI results.

• For ultra-high field MRI (7T) examination:

• Patients with leukoencephalopathy aged between 8 and 30 years, who are capable of cooperating with an MRI examination.

• Patients suffering from leukoencephalopathy, who have already undergone a clinical field MRI (=3T) as part of their diagnostic or research clinical pathway according to the diagnostic flowchart identified and shared with other institutes, and who present inconsistencies between clinical and imaging profiles or white matter patterns on clinical field imaging.

Exclusion Criteria:

• All subjects with absolute contraindications to undergoing an MRI exam, as determined by the medical history questionnaire.

• Patients with severe clinical conditions, such as the presence of a tracheostomy.

Additionally, further exclusion criteria for subjects participating in the 7T study will include:

• Age under 8 years;

• Inability to cooperate with undergoing an MRI exam.

Related Conditions & MeSH terms

• Leukoencephalopathies

Intervention

Diagnostic Test:
• Brain quantitative magnetic resonance imaging
Identification and predictability of early structural and metabolic markers from 3T and 7T quantitative magnetic resonance imaging (qMRI)

Locations

Country	Name	City	State
Italy	Fondazione Istituto Neurologico Carlo Besta	Milano
Italy	Ospedale San Raffaele	Milano
Italy	IRCCS Associazione Oasi Maria SS Troina	Troina	Enna

Sponsors (4)

Lead Sponsor	Collaborator
IRCCS Fondazione Stella Maris	Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, IRCCS Ospedale San Raffaele, Oasi Research Institute-IRCCS

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Quantitative Susceptibilty Mapping, QSM	The Relative magnetic susceptibility values (in units of parts per billions [ppb], with respect to water magnetic susceptibility) registered in subcortical structures and nuclei	every year for two years
Primary	Fractional Anisotropy, FA	FA values (a fractional number between 0 and 1), registered in lesioned white matter and normal-appearance white matter	every year for two years
Primary	Mean Diffusivity, MD	MD values (in units of square millimeters per second [mm²/s]), registered in lesioned white matter and normal-appearance white matter	every year for two years
Primary	Relaxation times	Values of longitudinal (T1) and transverse (T2) relaxation times (in units of milliseconds [ms]), registered in grey matter, lesioned white matter, normal-appearance white matter, and subcortical nuclei	every year for two years
Primary	Myelin water fraction, MWF	MWF values (a fractional number between 0 and 1), registered in grey matter, lesioned white matter, normal-appearance white matter, and subcortical nuclei	every year for two years
Primary	Neuromotor skills	Gross Motor Function Classification System (GMFCS) is a motor scale that categorizes patients' motor skills into 5 levels. Each level corresponds to a range of motor functions, with Level 1 representing mild symptoms and Level 5 being the most severe	every year for two years
Primary	Neuromotor skills	Movement Disorders-Childhood Rating Scale Revised (MD-CRS R) has a score ranging from 0 and 100 with deficits below 70	every year for two years
Secondary	Epilepsy symptoms	The presence of epilepsy symptoms (presence or absence)	every year for two years
Secondary	Electroencephalography features	Electroencephalography alteration (EEG-alteration) (presence or absence)	every year for two years
Secondary	Neuro-psychological profile	Wechsler Intelligence Scale for Children (WISC) has a score ranging from 0 and 100 with deficits below 70	every year for two years