Background/Objectives: Normal-appearing white (WM) and gray (GM) matter outside focal demyelinating lesions (WMH) has been found impaired in many diseases and normal aging. The present study aimed to compare global GM and WM alterations in patients with multiple sclerosis (MS), Parkinson's disease, long COVID (LC) and normal aging. Methods: The study population comprised 196 participants including patients with MS (n = 42), PD (n = 16), LC (n = 75), and healthy volunteers (n = 63). All participants underwent MR scanning using the fast macromolecular fraction (MPF) mapping protocol and routine clinical sequences. MPF in global normal-appearing WM, GM, and mixed WM-GM was measured after exclusion of segmented focal lesions. To eliminate the influence of gender, age, and brain atrophy on the results, the corresponding covariates were included in the analysis. Results: Significant WMH volume increase and MPF decrease in global WM, WM-GM, and GM were found both in normal aging (75-85 years) and MS, PD, and LC patients (except for WM and WMH volume in LC patients). The greatest MPF decrease was observed in MS patients. The youngest (18-24 years) controls had a significant MPF decrease in global WM, WM-GM, and GM compared to middle-aged (35-44 years) participants. Among LC patients, the greatest global MPF reduction was found in patients with depression and insomnia as COVID-19 complications. In healthy controls, the peak age of myelination was estimated as 42.2 years for WM, 46.5 years for WM-GM, and 45.4 years for GM. Significant correlations were found between MPF and EDSS in MS patients (r = -0.71 in GM, r = -0.58 in WM-GM, r = -0.44 in WM) and stage of PD in PD patients (r = -0.58 in GM, r = -0.55 in WM-GM, r = -0.52 in WM). Conclusions: MPF mapping showed high sensitivity to age-related and disease-related differences in brain myelination, particularly in GM. Our results confirm the feasibility of using MPF mapping in large-scale clinical studies.
