Contribution of Conventional and Quantitative MRI in Leukodystrophies
Authors:   , Stellingwerff Menno Daniël 
Published: October 2024

We explored the contribution of magnetic resonance imaging (MRI) in leukodystrophies. Leukodystrophies are genetic diseases mainly affecting the white matter of the central nervous system. A multitude of variants in many different genes can cause leukodystrophies; variants in each gene are related to a specific leukodystrophy, associated with specific underlying pathological changes. These disorders may cause devastating signs and symptoms. Since recently disease-specific therapies are emerging for several leukodystrophies.
In part I of the dissertation, we focus on conventional MRI techniques, based on comparing signal intensity between normal and abnormal tissue.
Chapter 1.1 and chapter 1.2 describe the natural MRI history of chronic decline and the imaging correlates of acute episodes of decline in the leukodystrophy “vanishing white matter” (VWM). In chapter 1.1, we conclude that the cerebral white matter abnormalities do not improve and reflect the chronic disease course of VWM. Patients with VWM may also suffer from acute episodes of neurological decline. The results in chapter 1.2 indicate that signal abnormalities in deep gray matter structures and the brain stem may appear with acute episodes of neurological decline, and may disappear after recovery of such episodes. These findings aid correct MRI interpretation in VWM patients.
In chapter 1.3 the clinical and MRI spectrum of the leukodystrophy “leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation” is broadened, a disease caused by variants in the DARS2 gene. We describe two atypical MRI patterns in 15 severely affected patients. One MRI pattern featured striking cerebral atrophy, and one had a lack of the typical brainstem abnormalities. We discuss that different specific DARS2 variants likely cause detrimental effects to different cell types in the white matter, leading to different disease characteristics.
Chapter 1.4 reports on three patients with clinical signs and the MRI pattern pointing to a vascular pathophysiology, in which a specific diagnosis lacked for many years. Genetic testing revealed biallelic NOTCH3 variants. These variants were first ignored, as NOTCH3 variants also cause CADASIL, in which they are mono-allelic. The patients described presented at a much earlier age, and lacked certain hallmarks of CADASIL, indicating that they have a different disease, albeit various similarities suggest a comparable pathophysiological pathway.
In part II of the dissertation, we focus on quantitative MRI techniques, aiming to probe microstructural properties.
Chapter 2.1 reviews numerous quantitative MRI techniques in the context of leukodystrophies. White matter consists of various cells and components. All can be affected in leukodystrophies. Certain quantitative MRI techniques aim to specifically extract microstructural information. This information may uncover neuropathological changes and aid in monitoring disease progression for different microstructural components separately. Most techniques are novel, and focus on a subset of tissue components.
In chapter 2.2 we implemented several promising quantitative MRI methods. Two techniques (MCR-DIMWI and METRICS) that quantify water bound to myelin were used and the results correlated strongly. The techniques are clinically feasible and show large differences between leukodystrophy patients and controls.
In chapter 2.3 we analyzed quantitative MRI in two distinct leukodystrophies with a fundamentally different pathology. The quantitative MRI measures distinguished between the leukodystrophies. Also, the degree of changes in quantitative MRI measures correlated to clinical measures, making the MRI measures relevant for monitoring.
In this dissertation we show the pivotal role of MRI in leukodystrophy research and clinical care. MRI is central in diagnosing patients, can identify new, as yet unknown diseases or variations of known diseases, and helps to generate hypotheses on disease processes and mechanisms. In the near future, quantitative MRI measures may act as biomarker in monitoring patients and may be used as secondary outcome measure in therapy trials.