Diffusion MRI (dMRI) is a technique for the non-invasive characterization of the microstructural
properties of biological tissues. Conventional dMRI methods, such as Diffusion Tensor Imaging
(DTI), rely on rather simple hypotheses relevant to hindered anisotropic diffusion homogeneous
within each voxel, which limit their sensitivity and specificity. To overcome these limits, several
advanced dMRI techniques have been developed; in particular multi-compartment models
disentangle hindered and restricted, isotropic and anisotropic diffusion. The aim of this work is
to investigate the feasibility and the potential benefits of multicompartment dMRI models in
clinical studies on neurological disease involving gray matter (GM) or white matter (WM), with
a translational approach. Three applications were tested: the study of gray matter alterations in
Creutzfeldt-Jakob Disease (CJD), the microstructural characterization of brain tumors and the
reconstruction of the trajectory of WM tracts (tractography) in patients with peritumoral edema.
In the first case, two possible neuropathological mechanisms were investigated and novel
biomarkers for CJD were provided, likely more sensitive and specific to this pathology than
usual DTI-derived measures. In the second application, the parameters derived from a multicompartment model allowed the characterization of different lesion component and the
differentiation of tumor grades better than DTI parameters. Finally, the use of a
multicompartment model allowed the robust reconstruction of WM tracts through areas of
peritumoral vasogenic edema, which is usually not possible with DTI-based tractography. In
conclusion, the application of dMRI multi-compartment models in clinical research is feasible
and can provide more accurate information about brain microstructure than traditional dMRI
methods.