Sirtuins and Metabolism Biomarkers in Relapsing-Remitting and Secondary Progressive Multiple Sclerosis: a Correlation Study with Clinical Outcomes and Cognitive Impairments

Multiple sclerosis (MS) is a primary inflammatory demyelinating disease with different clinical courses and subtypes. The present study aimed to determine whether mitochondrial dysfunction and sirtuins 1 and 3, as metabolism and epigenetic modifying factors, might contribute to MS disease progression measured by physical disability and cognitive impairment.The volunteers (n = 20 controls, n = 59 MS) were recruited and assessed for cognitive function and disability scores; then, patients were clinically classified as relapsing-remitting (RR) in remission phase, RR in relapse phase, and secondary progressive MS. We measured sirtuin (SIRT) 1 and 3 levels, mitochondrial complex I, IV, aconitase, and alpha-ketoglutarate dehydrogenase (alpha-KGD) activity in the peripheral blood mononuclear cells (PBMCs). Furthermore, SIRT1, pyruvate, lactate, and cytochrome c (Cyt c) were determined in plasma. Finally, we performed postmortem tissue immunohistochemistry to assess the level of SIRT1 and SIRT3 in the brain lesions of patients with MS.Increased disability and cognitive impairment in patients were correlated. Plasma level of lactate showed a correlation with the disability in MS patients; moreover, a trend toward increased Cyt c plasma level was observed. Investigation of PBMCs exhibited decreased SIRT1 during the relapse phase along with a reduced complex IV activity in all MS subgroups. alpha-KGD activity was significantly increased in the RR-remission, and SIRT3 was elevated in RR-relapse group. This elevation correlated with disability and cognitive impairment. Finally, immunohistochemistry demonstrated increased levels of SIRT1 and 3 in the brain active lesion of patients with MS.Our data suggest that mitochondrial dysfunction and alteration in some epigenetics and metabolism modifying factors in the CNS and peripheral blood cells may contribute or correlate with MS progression.