The importance of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) diagnosis is rapidly increasing, and there is a growing interest in the use of CSF biomarkers in monitoring the response to therapy, especially in the light of newly available approaches to the therapy of neurodegenerative diseases. In this review we discuss the most relevant measures of neurodegeneration that are being used to distinguish patients with AD from healthy controls and individuals with mild cognitive impairment, in order to provide an overview of the latest information available in the scientific literature. We focus on markers related to amyloid processing, markers associated with neurofibrillary tangles, neuroinflammation, neuroaxonal injury and degeneration, synaptic loss and dysfunction, and markers of α-synuclein pathology. In addition to neuropsychological evaluation, core CSF biomarkers (Aβ₄₂, t-tau, and p-tau181) have been recommended for improvement of timely, accurate and differential diagnosis of AD, as well as to assess the risk and rate of disease progression. In addition to the core CSF biomarkers, various other markers related to synaptic dysfunction, neuroinflammation, and glial activation (neurogranin, SNAP-25, Nfl, YKL-40, TREM2) are now investigated and have yet to be validated for future potential clinical use in AD diagnosis.

Major depressive disorder (MDD) is associated with complex metabolic alterations. In this study, we applied a multiplatform metabolomics approach (GC-MS and LC-MS) to characterize the plasma extracellular vesicle (EV) metabolome in healthy controls (N = 50), responsive MDD patients (N = 60), and patients with treatment-resistant depression (TRD; N = 65). Longitudinal analyses were performed following 8-week treatment with duloxetine (N = 30), bright-light therapy (BLT; N = 30), or esketamine (N = 35). A total of 230 metabolites were identified, with the most pronounced metabolic alterations observed in TRD patients, particularly in lipid, amino acid, and energy metabolism pathways. Elevated lysophospholipids and fatty acids in TRD suggested dysregulated lipid metabolism and inflammatory processes. All treatments resulted in clinical improvement, accompanied by partial normalization of metabolic profiles. Duloxetine treatment was associated with modulation of amino acid and glycerophospholipid metabolism, including increases in tryptophan-related metabolites and normalization of specific lipid species. BLT primarily reduced lysophospholipids and mannose levels, while esketamine modulated metabolites related to lipid turnover, short-chain fatty acids, carbohydrate metabolism, and neuroendocrine function, including increased thyrotropin-releasing hormone levels. These findings support the concept that TRD represents a biologically distinct and more metabolically dysregulated subtype of depression and highlight EV-based metabolomics as a promising approach for elucidating disease and treatment mechanisms.

Brain-derived neurotrophic factor (BDNF) plays a crucial role in cognitive functions and dementia. In individuals with mild cognitive impairment (MCI) and dementia, we have investigated BDNF Val66Met genotype distribution, peripheral BDNF DNA methylation, mRNA and protein levels, and cognitive performance using the Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT). Lower BDNF_IV1 methylation had predictive value for dementia. Patients with mild-to-moderate dementia had lower levels of BDNF_IV2 methylation, whereas patients with severe dementia had higher levels than the MCI group, while BDNF_IV2 methylation positively correlated with CDT scores. An insignificant decline in BDNF mRNA levels in dementia patients positively correlated with significantly lower BDNF plasma levels, especially pronounced in severe dementia patients. BDNF mRNA and protein levels were positively correlated with CDT and MMSE scores, respectively. BDNF Val66Met polymorphism was associated with methylation of the BDNF_IX amplicon, but not with methylation in BDNF promoters I and IV, peripheral BDNF gene and protein expression, MMSE and CDT scores, or dementia. Methylation at the BDNF Val66Met site was positively correlated with overall BDNF_IX methylation and methylation at 5 BDNF_IX CpG loci but negatively correlated with methylation of BDNF_IV1, BDNF_IV3, and BDNF_I1 amplicons. Further studies should evaluate the translational potential of these peripheral BDNF-based biomarkers for dementia.