Continuing development of novel brain treatments, which aim to overcome blood-brain barriers (BBB), further emerges the need to establish prognostic magnetic resonance (MR) markers to track progressive central nervous system (CNS) deficits in lysosomal storage diseases(LSD). Excessive intracellular accumulation of disease-specific substrates triggers significant CNS deficits that, in contrast to somatic organ damage, cannot be corrected by current therapies due to limited BBB permeability. While rare disease patients exhibit various cognitive and neurological deficits accompanied by different extents of morphological brain abnormalities such as brain shrinkage, gliosis, or enlarged perivascular spaces ranging, microstructural and metabolic processes have not been identified yet. The recent advancement in high and ultra-high field Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) opened up the possibility of monitoring tissue metabolism in exceptional detail. Thus, we addressed existing drawbacks and developed a comprehensive combination of reliable and reproducible techniques for mapping of the subtle yet clinically significant brain and spinal cord (SC) deficits. Methods allowed to quantify levels of microstructural, functional, and metabolic tissue damage and to distinguish areas affected by oxidative stress, inflammation, and cellular brain damage with exceptional accuracy. We were able to delineate significant deficits in the primary excitatory neurotransmitter in the posterior cingulate cortex that activates during the brain's rest and causes attention deficits seen in rare disease patients. The innovative 3D novel MRSI also depicted deficits in myelin turnover that resulted in microstructural disruptions in the white matter that responds to the efficient connection between major brain centers. We have also established MR protocol for the cervical SC to identify potentially life-threatening processes in patients with mucopolysaccharidosis and Pompe disease. Our methods addressed challenges due to small SC size and its anatomical localization. Thus, we were able to delineate symptomatic SC deficits before they appear on standard clinical MR techniques and provided measures for future trials. Indeed, reproducible and reliable MR methods established in our project allow assessing the effects of novel treatments such as intrathecal enzyme administration, chaperones, and gene therapies. Increased understanding of CNS pathology also promises to critically boost the search for optimal therapies in age-related neurodegenerative diseases such as Alzheimer's or Parkinson's or patients with spinal cord injury, degenerative spinal cord compression, and multiple sclerosis.
