Background. Oxidative stress is well documented in multiple sclerosis (MS) lesions, but its correspondence at peripheral level is still controversial. Objective. To evaluate peripheral oxidative stress markers in MS patients. Methods. We studied total blood levels of Coenzyme Q10 (CoQ10), oxidized and reduced forms of glutathione, malondialdehyde, reactive oxygen species (ROS), anti-oxidized-low-density lipoproteins (anti-oxLDL) antibodies, and antioxidant power (PAO) in 87 patients with different MS clinical phenotypes and in 77 controls. Results. CoQ10 was lower whereas anti-oxLDL antibodies titer was higher in MS patients than in controls. The benign variant of MS displayed both higher CoQ10 and higher anti-oxLDL than other MS clinical variants. Female patients had lower CoQ10 and PAO and higher ROS than male patients. Differences were greater in younger patients with shorter disease duration. Surprisingly, there was no difference for these markers between treated and untreated patients. Conclusion. We found lower antioxidant agents and higher anti-oxLDL antibodies in MS, and the highest antibody titers occurred in the benign form. We suggest that natural anti-oxLDL antibodies can be protective against MS, saving blood brain barrier integrity. Our findings also suggest that milder MS is associated with a distinct oxidative stress pattern, which may provide a useful biomarker of disease prognosis.

Background: Byproducts of oxidative metabolic reactions could play a role in the pathogenesis of several neurodegenerative diseases (ND) including Alzheimer’s disease (AD). We designed a study aimed at investigating a large set of oxidative and antioxidant markers in a sample of patients affected by different forms of dementia or memory impairment. Methods: Serum levels of coenzyme Q₁₀, malondialdehyde (MDA), the total, oxidized and reduced forms of glutathione (GStot, GSSG and GSH, respectively), reactive oxygen species, anti-oxidized low-density lipoprotein antibodies and antioxidant power (PAO) were investigated in patients affected by AD, mild cognitive impairment, dementia with Lewy bodies and Parkinson’s disease with dementia. The patient sample (n = 66) was compared with healthy subjects (HC; n = 62), and a comparison across pathological subgroups was also performed. A multivariate logistic regression model was implemented in order to calculate an algorithm model for predicting the risk of developing a neurodegenerative disorder. Results: The comparison between the memory deficit (MD) group and HC showed a significant difference for MDA (MD: 6.3 ± 2.8 µg/l; HC: 9.1 ± 4.9 µg/l; p = 1.7 × 10^–6), GStot (MD: 260.4 ± 62.6 mg/l; HC: 306.5 ± 60.7 mg/l; p = 2.2 × 10^–5), GSH (MD: 208.9 ± 68.4 mg/l; HC: 295.3 ± 101.3 mg/l; p = 2.2 × 10^–7) and PAO (MD: 1,066.5 ± 247.7 µmol; HC: 954.9 ± 200.4 µmol; p = 0.8 × 10^–3). By contrast, no differences in the levels of the studied markers were detected across the different forms of ND. An older age, higher levels of PAO, lower levels of GSH and MDA and the use of cardiovascular or antidepressant drugs were the most important factors associated with the carrier ship of neurodegenerative disorder. Conclusion: To our knowledge, this is the first study reporting similar oxidative imbalance in different forms of memory impairment, regardless of the specific etiology. Low GSH levels could be considered as a favorable factor in ND; at the same time it could be suggested that higher levels of PAO represent a counteracting mechanism against an increased oxidative stress. The association between vascular risk factors, depressive status and cognitive impairment is in line with findings in the literature.

Alzheimer's disease (AD) is the most common form of dementia, while mild cognitive impairment (MCI) causes a slight but measurable decline in cognitive abilities. A person with MCI has an increased risk of developing AD or another dementia. Thus, it is of medical interest to develop predictive tools to assess this risk. A growing awareness exists that pro-oxidative state and neuro-inflammation are both involved in AD. However, the extent of this relationship is still a matter of debate. Due to the expected non-linear correlations between oxidative and inflammatory markers, traditional statistics is unsuitable to dissect their relationship with the disease. Artificial neural networks (ANNs) are computational models inspired by central nervous system networks, capable of machine learning and pattern recognition. The aim of this work was to disclose the relationship between immunological and oxidative stress markers in AD and MCI by the application of ANNs. Through a machine learning approach, we were able to construct an algorithm to classify MCI and AD with high accuracy. Such an instrument, requiring a small amount of immunological and oxidative-stress parameters, would be useful in the clinical practice. Moreover, applying an innovative non-linear mathematical technique, a global immune deficit was shown to be associated with cognitive impairment. Surprisingly, both adaptive and innate immunity were peripherally defective in AD and MCI patients. From this study, new pathogenetic aspects of these diseases could emerge.

M.R. and R.E contributed equally to this workReactive oxygen species(ROS) are mainly produced by microglia and macrophages during inflammationdriven oxidative burst. However, they can in turn affect the reactivity and function ofimmune cells.For the first time, the relationship between these two key players involved in Multiple Sclerosis (MS) was evaluated at peripheral level. We performed an in-depth immune-phenotypic and functional analysis ofMBP (Myelin Basic Protein)-stimulated Peripheral Blood Mononuclear Cells (PBMCs) by flow-cytometry. In addition, blood Coenzyme-QI0 (CoQI0), total, oxidized and reduced forms of glutathione (GSTot, GSSG, GSH), malondialdehyde (MDA), ROS, anti-oxidized-low-density-lipoproteins antibodies (anti-oxLDL), and anti-oxidant-power (PAO) were studied in 31 untreated MS patients (MSnoTP), 23 MS patients (MSTP) treated with Disease Modifying Drugs (DMDs) and 39 matched controls (HC). The focus of our study was the correlation between oxidative stress biomarkers and distribution of immune-phenotypes across the 3 studied groups. In MSnoTP an inverse correlation between MDA and apoptotic cells (CD4+ AnnexinV+ TIM3+) was detected (rs= -0.50, p= 0.01). Ml functional phenotype (CDI4+ IL6+) and TH17 cells (CD4+ IL22+) inversely (rs= -0.48) and directly (rs= 0.46) correlated (p = 0.01) with Anti-oxLDL antibodies and GSSG, respectively. The latter direct correlation was shown also in MSTP. Notably, in this group, we also detected a direct correlation between CD4+ IL4+ and CD4+ IL25+ (TH2 phenotype) with CoQI0 (rs= 0.54) and GSH (rs= 0.46) (p< 0.03), two crucial anti-oxidants. Again, a direct correlation was found between CD8+ BDNF+ cells (suppressor phenotype) and anti-oxLDL (rs= 0.48, p= 0.03). Surprisingly, we measured an inverse correlation between CDI4+ ILI0+ cells (M2 immune-regulatory cells) with GSH (rs= -0.59, p< 0.001). Our findings endorse the idea of a relationship between pro-inflammatory cells and pro-oxidative environment, even at peripheral level. Interestingly, the correlation between CD4+ ILIO+ cells and a defective anti-oxidant equipment might be regarded as evidence of the involvement of these cells during an inflammatory/oxidative phase that they try to control. The finding ofthis link only in MSTP patients might suggest that DMDs can provide an alternative way to counteract inflammation, regardless of an absolute increase of these immune-regulatory cells.

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