"Direct Access Physiotherapy and Medical Task Sharing and Shifting, I'm on Board, But There Are Some Caveats": A Qualitative Study Exploring Family Physicians' Conditional Acceptability and Perception

Wilson disease (WD) is a rare autosomal-recessive disorder of impaired copper metabolism that leads to pathological copper accumulation in the liver and brain, and may result in hepatic dysfunction, neurological impairment, and cognitive deficits. The most affected cognitive domains are memory, attention, processing speed, verbal fluency, and executive function. Neurological manifestations in WD are associated with poorer prognosis and significantly reduced health-related quality of life compared with the hepatic form of the disease, largely attributable to cognitive decline. Cerebral copper accumulation induces neurotoxic damage in the brain, primarily affecting deep gray matter nuclei and white matter (WM) tracts. While a growing body of research has documented the clinical significance of basal ganglia impairments in WD, only a limited number of studies have investigated the relationship between WM integrity and clinical symptoms. Thus, the role of WM alterations in WD-related neurological and cognitive impairment remains poorly understood. The evaluation of WM in WD is predominantly based on diffusion tensor imaging (DTI), which characterizes brain microstructure using diffusion-weighted magnetic resonance imaging (MRI) by quantifying the directional motion of water molecules. These studies have reported widespread disruption in fiber integrity in WD, primarily reflected by reduced fractional anisotropy (FA) and increased mean diffusivity (MD), measuring the overall directionality and magnitude of water diffusion, respectively. Despite the high sensitivity of DTI metrics to WM damage, their limited biological specificity leaves the underlying pathomechanisms unclear. In addition, a recent study demonstrated increased free water content in the WM of WD patients and a marked attenuation of DTI abnormalities following free water correction. Free water contamination, arising from partial volume effects between, e.g., cerebrospinal fluid and brain parenchyma within a voxel, may bias DTI measurements and contribute to inconsistencies in DTI findings across WD studies, particularly regarding the direction of FA changes. Given its lack of specificity and susceptibility to partial volume effects, especially in regions with complex fiber architecture or inter-tissue interactions, conventional DTI may be insufficient to fully characterize WM pathologies in WD. Recent advancements in diffusion MRI modeling have introduced neurite orientation dispersion and density imaging (NODDI) as a promising candidate for the development of next-generation imaging biomarkers of neuronal microstructure impairment. In contrast to the single-tensor model used in DTI, NODDI decomposes the diffusion signal into three distinct tissue compartments. Thereby, specific estimates of neurite density, neurite orientation dispersion, and free water proportion are derived, which are expected to provide biologically more meaningful information. Application of NODDI has yielded encouraging results in clinical research, demonstrating high sensitivity and plausible interpretations of disease-related effects, as well as robust correlations with disease severity in patients with Alzheimer’s or Parkinson’s disease. Preliminary NODDI studies in WD patients indicate significant microstructural impairment in the basal ganglia, thalamus, and WM. However, the current evidence is scarce, particularly with respect to phenotype-specific changes, and the relationship between NODDI-derived WM metrics and clinical symptoms has not yet been investigated in WD.