Periodic Reporting for period 1 - NeuroLSD (Neuro-metabolic, structural and functional hallmarks of Lysosomal Storage Diseases)
Reporting period: 2018-10-01 to 2020-09-30
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.
During the project, we established 7T and 3T brain protocols to delineate early deficits in Mucopolysaccharidosis (MPS), Galactosemia, Phenylketonuria, Gaucher, and Pompe diseases. We depicted regions for single-voxel MR spectroscopy (MRS), selecting the posterior cingulate cortex for patients with cognitive deficits and putamen and cerebellum in those affected by neurological symptoms for comparison with 3D-MRS imaging (MRSI). We addressed challenges caused by anatomically altered CNS by the utilization of innovative lipid suppression, motion correction, and shimming techniques. Novel 3D-MRSI addressed the downsides of the single-voxel MRS techniques while providing high-quality, reproducible spectra from whole brain. 3D-MRSI outcomes corroborated changes of major excitatory brain metabolite detected by single-voxel MRS while depicting increased myelin turnover in the white matter (WM) that would otherwise remain hidden. The metabolic alterations led to microstructural deficits and resulted in psychological and neurological alterations. Additional cervical spinal cord (CSC) imaging was needed to delineate life-threatening CSC damage in MPS and Pompe patients. Ongoing CSC deficits still have not been described due to the challenges caused by small CSC size and pronounced susceptibility artifacts. Thus, we developed novel acquisition techniques to unravel metabolic and microstructural CSC deficits and provided more specific tract-based analysis, which depicted deficits that would remain undetected using traditional analysis techniques. We also established timesaving multiparametric quantitative MR fingerprinting to quantify CSC alterations such as demyelination, axonal loss, or glial scarring. Our work thus overcomes the project's main objective when providing reproducible brain and CSC MRI/MRS in rare diseases for longitudinal trials. Outcomes were published in journals with high impact or are currently in preparation for submission. Our work was enthusiastically received by the scientific community when awarded Magna Cum Laude from the International Society for MR in medicine and pharmacological industry, with longitudinal projects being already submitted. We have established an excellent collaboration with patients' organizations and clinicians, and the project outcomes will be further disseminated through seminars and disease awareness days. We will utilize fruitful collaborations with Lysosomal Disease Network and European Centers to set multicentric studies in rare diseases. Our work thus provided quantitative measures of the abnormal CNS in rare diseases for longitudinal clinical trials.
Our project evaluated, for the first time, the feasibility of advanced magnetic resonance imaging (MRI) and spectroscopy (MRS) to quantify metabolic, microstructural, and functional deficits in gray and white matter (WM) of Mucopolysaccharidosis, Pompe, Gaucher, Galactosemia and Phenylketonuria patients. The ultra-short echo 3D MRS imaging (MRSI) method overcomes critical drawbacks of current single-voxel MRS, particularly the limited spatial coverage, which is unsuitable for diseases with an unknown metabolic alteration. Successful minimization of movement artifacts combined with advanced lipid suppression improved detection sensitivity, enabled applicability of MRSI in patient populations, and obtained spectral quality comparable to the single-voxel MRS approach, covering the whole brain instead of a small 8ml area. Thus, the 3D-MRSI method corroborated deficits detected by single-voxel MRS while additionally depicted alterations in myelin turnover in WM that led to microstructural and functional changes. Novel MRSI thus provided an easy-to-apply method for robust and reliable mapping of metabolic disturbances for rare diseases that can be easily translated to other neurological and psychiatric disorders. The recent MRSI advancements promise to expand the 7T methods to the 3T scanner and further boost its applicability and scientific impact. In addition, an advanced protocol for cervical spinal cord (CSC) imaging was developed to quantify deficits leading to life-threatening CSC symptoms in patients. Our advanced acquisition and analysis techniques provided completely novel quantitative methods and selective tract-based analysis to evaluate symptomatic CSC alterations that cannot be distinguished at the morphological MRI. Protocol might also be implemented in patients with spinal cord compression, spinal cord injury, or amyotrophic lateral sclerosis. Thus, we established reliable and reproducible protocols for brain and CSC alteration in rare diseases while addressing challenges introduced by the movement or abnormal macrostructure and offered markers for clinical trials.