METABOLOMIC AND LIPIDOMIC STUDIES IN DEGENERATIVE AND AGE-RELATED DISEASES

This translational research program is designed to identify and validate metabolomic and lipidomic molecular biomarkers for early diagnosis, prognostic stratification, and therapeutic monitoring in degenerative and age-related disorders. A central focus has been the investigation of oxysterols as pivotal intermediates within the cholesterol–oxidative stress–target-organ injury axis. The first two studies included 14 individuals with Alzheimer’s disease dementia (three of whom carried an NPC1 mutation), 22 individuals with non-Alzheimer’s dementias, and 53 cognitively unimpaired controls. The third study enrolled 54 patients with arterial hypertension and 150 normotensive participants. In the first two studies, cerebrospinal fluid analyses revealed a selective increase in non- enzymatically generated oxysterols and cholesterol biosynthetic intermediates in both Alzheimer’s and non-Alzheimer’s dementias, delineating a metabolomic signature associated with neurodegenerative pathology. In the three familial cases of autosomal dominant Alzheimer’s disease linked to a heterozygous NPC1 mutation, Miglustat treatment was associated with a reduction in cerebral amyloid burden, normalization of oxysterol profiles, and clinical stabilization. In the hypertension cohort, integrated metabolomic–lipidomic profiling disclosed significant perturbations not only in hypertensive patients but also in individuals with early normotensive phenotypes, characterized by a marked depletion of polyunsaturated fatty acids: Eicosapentaenoic Acid, Docosahexaenoic Acid, and Arachidonic Acid) and very-long-chain fatty acids. These findings suggest that lipidomic derangements may precede the overt clinical manifestation of hypertension, potentially contributing to vascular and myocardial remodeling and serving as candidate early biomarkers of cardiovascular risk. Moreover, hypertensive subjects exhibited increased 7β- hydroxycholesterol levels, which correlated closely with established indices of cardiovascular target-organ damage, including pulse wave velocity, carotid intima–media thickness, and left ventricular mass index. Collectively, these results substantiate a relevant pathogenetic contribution of lipid dysregulation to the neurodegenerative and cardiovascular processes of aging and indicate that the integration of metabolomic, lipidomic, and clinical data constitutes a rigorous methodological platform for the development of translational biomarkers and precision therapeutic strategies.