Consensus Paper: Radiological Biomarkers of Cerebellar Diseases

Hereditary and sporadic cerebellar ataxias represent a vast and still growing group of diseases whose diagnosis and differentiation cannot only rely on clinical evaluation. Brain imaging including magnetic resonance (MR) and nuclear medicine techniques allows for characterization of structural and functional abnormalities underlying symptomatic ataxias. These methods thus constitute a potential source of radiological biomarkers, which could be used to identify these diseases and differentiate subgroups of them, and to assess their severity and their evolution. Such biomarkers mainly comprise qualitative and quantitative data obtained from MR including proton spectroscopy, diffusion imaging, tractography, voxel-based morphometry, functional imaging during task execution or in a resting state, and from SPETC and PET with several radiotracers. In the current article, we aim to illustrate briefly some applications of these neuroimaging tools to evaluation of cerebellar disorders such as inherited cerebellar ataxia, fetal developmental malformations, and immune-mediated cerebellar diseases and of neurodegenerative or early-developing diseases, such as dementia and autism in which cerebellar involvement is an emerging feature. Although these radiological biomarkers appear promising and helpful to better understand ataxia-related anatomical and physiological impairments, to date, very few of them have turned out to be specific for a given ataxia with atrophy of the cerebellar system being the main and the most usual alteration being observed. Consequently, much remains to be done to establish sensitivity, specificity, and reproducibility of available MR and nuclear medicine features as diagnostic, progression and surrogate biomarkers in clinical routine

Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies

Magnetic resonance imaging pattern recognition in hypomyelinating disorders

Hypomyelination is observed in the context of a growing number of genetic disorders that share clinical characteristics. The aim of this study was to determine the possible role of magnetic resonance imaging pattern recognition in distinguishing different hypomyelinating disorders, which would facilitate the diagnostic process. Only patients with hypomyelination of known cause were included in this retrospective study. A total of 112 patients with Pelizaeus-Merzbacher disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, Pelizaeus-Merzbacher-like disease, infantile GM1 and GM2 gangliosidosis, Salla disease and fucosidosis were included. The brain scans were rated using a standard scoring list; the raters were blinded to the diagnoses. Grouping of the patients was based on cluster analysis. Ten clusters of patients with similar magnetic resonance imaging abnormalities were identified. The most important discriminating items were early cerebellar atrophy, homogeneity of the white matter signal on T-2-weighted images, abnormal signal intensity of the basal ganglia, signal abnormalities in the pons and additional T-2 lesions in the deep white matter. Eight clusters each represented mainly a single disorder (i.e. Pelizaeus-Merzbacher disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, infantile GM1 and GM2 gangliosidosis, Pelizaeus-Merzbacher-like disease and fucosidosis); only two clusters contained multiple diseases. Pelizaeus-Merzbacher-like disease was divided between two clusters and Salla disease did not cluster at all. This study shows that it is possible to separate patients with hypomyelination disorders of known cause in clusters based on magnetic resonance imaging abnormalities alone. In most cases of Pelizaeus-Merzbacher disease, hypomyelination with congenital cataract, hypomyelination with hypogonadotropic hypogonadism and hypodontia, Pelizaeus-Merzbacher-like disease, infantile GM1 and GM2 gangliosidosis and fucosidosis, the imaging pattern gives clues for the diagnosis