In this review, the potential causes of ageing are discussed. We seek to gain insight into the main physiological functions of mitochondria and discuss alterations in their function and the genome, which are supposed to be the central mechanisms in senescence. We conclude by presenting the potential modulating role of the kynurenine pathway in the ageing processes. Mitochondrial dynamics are supposed to have important physiological roles in maintaining cell homeostasis. During ageing, a decrease in mitochondrial dynamics was reported, potentially compromising the function of mitochondria. Mitochondrial biogenesis not only encompasses mitochondrial dynamics, but also the regulation of transcription and translation of genes, and mitochondria are supposed to play a prominent role in cell death during senescence. Defects in the mtDNA replication machinery and failure in the repair of mtDNA might result in the accumulation of mutations, leading to mitochondrial dysfunction and bioenergetic failure of the cell. The role of reactive oxygen species (ROS) in the ageing processes is widely acknowledged. Exaggerated oxidative damage to mDNA is supposed to take place during senescence, including single-nucleotide base alterations, nucleotide base pair alterations, chain breaks and cross linkage. A broad repertoire for the repair of DNA faults has evolved, but they do not function efficiently during senescence. Poly (ADP-ribose) polymerase (PARP) is an enzyme that assists in DNA repair, i.e., it participates in the repair of single-stranded DNA nicks, initiating base excision repair (BER). In the case of extensive DNA damage, PARP-1 becomes overactivated and rapidly depletes the intracellular NAD+ and ATP pools. This results in a profound energy loss of the cell and leads to cell dysfunction, or even cell death. Alterations in the kynurenine system have been linked with ageing processes and several age-related disorders. The kynurenine pathway degrades tryptophan (TRP) to several metabolites, among others kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN). The end product of the route is NAD+. The first metabolic reaction is mediated by TRP-2,3-dioxygenase (TDO) or indolamine-2,3-dioxygenases (IDO), the latter being induced by inflammation, and it is thought to have a significant role in several disorders and in ageing. Research is currently focusing on the KYN pathway, since several intermediates possess neuro- and immunoactive properties, and hence are capable of modulating the activity of certain brain cells and inflammatory responses. During ageing, and in many age-associated disorders like obesity, dyslipidaemia, hypertension, insulin resistance and neurodegenerative diseases, low-grade, sustained inflammation and upregulation of IDO have been reported. However, TRP downstream catabolites create a negative feedback loop by weakening the activated immune system through several actions, including a decline in the Th1 response and an enhancement of Th2-type processes. The broad actions of the KYN-intermediat...

The simultaneous quantitative estimation of tryptophan (TRP) and its metabolites represents a great challenge because of their diverse chemical properties, e.g., presence of acidic, basic, and nonpolar functional groups and their immensely different concentrations in biological matrices. A short ultra high-performance liquid chromatography (UHPLC)-tandem mass spectrometry (MS/MS) method was validated for targeted analysis of TRP and its 11 most important metabolites derived via both kynurenine (KYN) and serotonin (SERO) pathways in human serum and cerebrospinal fluid (CSF): SERO, KYN, 3-hydroxyanthranilic acid, 5-hydroxyindoleacetic acid, anthranilic acid, kynurenic acid (KYNA), 3hydroxykynurenine (3-HK), xanthurenic acid, melatonin, picolinic acid (PICA), and quinolinic acid (QUIN). After selecting the "best" reversed-phase column and organic modifier, DryLab ® 4 was used to optimize the gradient time and temperature in chromatographic separation. To achieve absolute quantification, deuterium-labeled internal standards were used. Among all compounds, 3 were analyzed in derivatized (butyl ester) forms (3-HK, PICA, and QUIN) and the remaining 9 in underivatized forms. Validation was performed in accordance with the ICH and FDA guidelines to determine the intraday and interday precision, accuracy, sensitivity, and recovery. To demonstrate the applicability of the developed UHPLC-MS/MS method, the aforementioned metabolites were analyzed in serum and CSF samples from patients with multiple sclerosis (multiple sclerosis group) and those with symptomatic or noninflammatory neurological diseases (control group). The concentration of QUIN dramatically increased, whereas that of KYNA slightly decreased in the multiple sclerosis group, resulting in a significantly increased QUIN/KYNA ratio and significantly decreased PICA/QUIN ratio.

Diffuse midline gliomas, H3 World Health Organization (WHO) grade IV represent a distinct glioma entity with a predominantly paediatric presentation and remarkably poor prognosis. This report presents a case of a 73-year-old woman with a diffuse midline glioma, H3 K27M-mutant, WHO grade IV with a remarkable longitudinal extension, extending from the cervical myelon to the basal ganglia. On imaging, the lesion was predominantly suggestive of inflammatory oedema, and it was clinically associated with progressive hemi-and later tetraparesis with severe autonomic and bulbar symptoms. Laboratory examinations suggested a generalized inflammatory process; however, neither infectious nor autoimmune aetiology could be confirmed. Biopsy was deemed unfeasible given the critical localization. Presuming a seronegative autoimmune encephalomyelitis, high-dose corticosteroid therapy and plasma exchanges were conducted, resulting in a modest but transient relief. The patient passed away two months after hospitalization. Neuropathological examination of the lesion revealed a high-grade diffuse glioma with H3 K27M mutation (grade IV). Although originally considered as a paediatric entity, our case confirms reports from recent years that diffuse midline gliomas, H3 K27M-mutant, WHO grade IV can occur in adults, even among the elderly, and can mimic inflammatory alterations, posing diagnostic difficulty. Our case is one of the oldest patients reported with this pathology, the oldest with an extensive diffusely infiltrating growth pattern, and with the most extensive lesion reported in adulthood.

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Introduction: There are conflicting results in the literature regarding the connection between thrombophilias and ischaemic stroke. However, most of the clinical studies have not differentiated between various ischaemic stroke subtypes. Our aim was to investigate whether there is an association between the methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism and ischaemic stroke due to small vessel disease (SVD) in patients 50 years of age. Patients and methods: We performed a retrospective search in the database used at our Health Centre. Our study population consisted of 100 ischaemic stroke patients. 65 patients had MTHFR C677T variants: 21 were homozygous (TT allele), 45 were heterozygous (CT). 35 stroke patients did not carry MTHFR C677T polymorphism (wild genotype, CC). Stroke subtypes were determined according to the TOAST classification. Pearson's chisquared test of independence was used to evaluate differences between subgroups and multivariate logistic regression was also performed. Results: More than half of our study population (52.00%) had lacunar strokes. The ratio of SVD in patients 50 years of age with TT homozygous variant was significantly higher compared to heterozygous and wild type subjects (p ¼ 0.032 and p ¼ 0.03 respectively). Multivariate logistic regression also showed, that apart from hypertension, only TT homozygosity was a predictive factor for SVD related stroke (p ¼ 0.014, OR 1.619, 95% CI 1.390-18.338). Conclusion: Our results demonstrate that in a Hungarian population of ischaemic stroke patients 50 years of age, SVD is the most common stroke subtype. In addition, we found association of SVD stroke with hypertension and MTHFR 677TT homozygous polymorphism.

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