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

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.


Eligibility Criteria:
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.