Validation of a Prognostic Biomarker Using Brain Diffusion MRI in X-linked Adrenoleukodystrophy (CALDIFF)

X-linked adrenoleukodystrophy (ALD, ORPHA:43, prevalence 1/15,000) is a rare white matter degenerative disease caused by pathogenic variants in the ABCD1 gene localised on the X chromosome. All men carrying ABCD1 pathogenic variants develop a slowly progressive myeloneuropathy (adrenomyeloneuropathy, AMN) in adulthood. Furthermore, men carrying ABCD1 pathogenic variants may also present with a rapidly progressive inflammatory leukodystrophy called cerebral ALD (CALD). Because ABCD1 variants do not predict the risk of CALD, the current standard of care is to annually monitor disease evolution by performing brain MRI and clinical evaluation to detect CALD conversion.

In adults, the inconsistency of Gadolinium contrast enhancement - the main CALD diagnosis criterion - and the presence of diffuse increase in signal of the white matter related to AMN, make the detection of true inflammatory hypersignals of the white matter (scored with the Loes score) increasingly difficult, and subject to inter-observer and inter-machine variability. Due to these limitations, and since standard MRI does not quantify myelin content or axonal injury, expert centres complement their imaging data with a battery of clinical tests - i.e., Adult ALD Clinical Scale (AACS) and Expanded Disability Severity Score (EDSS) - and neuropsychological testing to determine the disease stage of each patient with the aim to propose the best therapeutic options.

When CALD is not treated, inflammatory demyelinating lesions will cause severe motor and cognitive deficit and patients bear the risks to die within 2 to 3 years. The medical procedure of choice for males with CALD is allogenic hematopoietic stem cell transplantation (AlloHSCT) as it can stop the progression of demyelinating lesions, but only if performed during the early phase of the disease, when patients have minimal brain lesions and no or minor clinical symptoms. This treatment is ineffective or even harmful in patients in advanced stages due to the toxicity related to myeloablation protocols. In the current standard of care, the lack of early diagnostic biomarkers of CALD hampers the optimal use of AlloHSCT resulting in almost 50% mortality in adults developing CALD.

Thus, there is a crucial need for novel sensitive techniques or biomarkers easily deployable in clinical routine allowing to identify as early as possible the acute demyelinating process underlying CALD conversion.

This study aims to validate the use of an imaging biomarker, RD-index19-change, as an early diagnostic biomarker for CALD. This marker is an integrated measure of changes in cerebral regional radial diffusivity (RD) calculated from Diffusion Tensor Imaging (DTI). The RD-index19-change biomarker available in brainTale-care, a medical device developed by brainTale, can be automatically computed from MRI acquisition data in clinical routine.

The study aims to demonstrate that RD-index19-change of at least 1 point between two consecutive annual measurements has a sensitivity significantly greater than 60% and specificity significantly greater than 80%, as Objective Performance Criteria, to detect CALD conversion before or at the same time as the best experts in the field of CALD diagnosis.

The reference diagnosis of CALD will be established by an expert committee comprising 3 experts in neuroradiology, white matter diseases and CALD, based on the following information:

* One-year progression of white matter brain lesions as quantified by a Loes score change and/or the appearance of Gadolinium enhancement. The Loes scoring will be performed by an expert neuroradiologist trained to identify specific ALD lesion changes. Experts will have access to FLAIR and T1 pre- and post-contrast images. * Increase of AACS, and especially the cerebral domain of AACS, C-AACS. * The general disability scale EDSS * Neuropsychological tests to evaluate processing speed, recall memory, anxiety (State-Trait Anxiety Inventory) and depression (Beck Depression Inventory)

In order for the reference diagnosis to be independent of the biomarker results, the expert committee will be blinded to the results of RD-index19-change.

The experts will also be blinded to the results of other potential biomarkers of CALD conversion that will be evaluated as secondary endpoints, i.e., plasma NfL and other DTI biomarkers (FA-index19-change, MD-index19-change and AD-index19-change).

RD-index19\_change from yearly visit to yearly visit will be automatically computed from DTI acquisitions. It will therefore be independent from any clinical information or expert assessment.

The confirmation by this study that RD-index19-change can reliably detect CALD at an early stage of cerebral demyelination in an expert-independent manner will allow that:

* More CALD patients can be detected early enough to undergo AlloHSCT. The RD-index19-change should at least double the number of patients efficiently treated for this devastating neurodegenerative condition. * Thanks to the early detection using the RD-index19-change, patients will face a decreased risk of morbidity and mortality due to AlloHSCT itself * Patients can be followed wherever they live in France as the acquisition of MRI data for RD-index19-change calculation can be achieved on every local MR scanner after simple initial calibration. * Besides the validation of the RD-index19-change, the CALDIFF study will greatly increase the awareness of patients, but also neurologists, about the risk of CALD in ABCD1-mutated men on a nationwide scale