Chlamydophila pneumoniae Infection and Its Role in Neurological Disorders

Chlamydophila pneumoniae is an intracellular pathogen responsible for a number of different acute and chronic infections. The recent deepening of knowledge on the biology and the use of increasingly more sensitive and specific molecular techniques has allowed demonstration of C. pneumoniae in a large number of persons suffering from different diseases including cardiovascular (atherosclerosis and stroke) and central nervous system (CNS) disorders. Despite this, many important issues remain unanswered with regard to the role that C. pneumoniae may play in initiating atheroma or in the progression of the disease. A growing body of evidence concerns the involvement of this pathogen in chronic neurological disorders and particularly in Alzheimer's disease (AD) and Multiple Sclerosis (MS). Monocytes may traffic C. pneumoniae across the blood-brain-barrier, shed the organism in the CNS and induce neuroinflammation. The demonstration of C. pneumoniae by histopathological, molecular and culture techniques in the late-onset AD dementia has suggested a relationship between CNS infection with C. pneumoniae and the AD neuropathogenesis. In particular subsets of MS patients, C. pneumoniae could induce a chronic persistent brain infection acting as a cofactor in the development of the disease. The role of Chlamydia in the pathogenesis of mental or neurobehavioral disorders including schizophrenia and autism is uncertain and fragmentary and will require further confirmation

Increased age and male sex are independently associated with higher frequency of blood–cerebrospinal fluid barrier dysfunction using the albumin quotient

Background: The cerebrospinal fluid (CSF)/serum quotient of albumin (QAlb) is the most used biomarker for the evaluation of blood–cerebrospinal fluid barrier (B-CSF-B) permeability. For years QAlb was considered only as an age-related parameter but recently it has also been associated to sex. The aim of the present study was to explore the impact of sex in the determination of B-CSF-B dysfunction. Methods: The analysis was retrospectively conducted on subjects consecutively admitted to the neurological ward. CSF and serum albumin levels were measured by immunonephelometry and pathological QAlb thresholds were considered: 6.5 under 40 years, 8.0 in the age 40–60 and 9.0 over 60 years. Results: 1209 subjects were included in the study. 718 females and 491 males (age: 15–88 years): 24.6% of patients had a diagnosis of multiple sclerosis, 23.2% suffered from other inflammatory neurological diseases, 24.6% were affected by non-inflammatory neurological diseases, and for 27.6% of patients the final neurological diagnosis could not be traced. Dysfunctional B-CSF-B was detected more frequently (44 vs. 20.1%, p < 0.0001) and median QAlb value were higher (7.18 vs. 4.87, p < 0.0001) in males than in females in the overall study population and in all disease sub- groups. QAlb and age were positively correlated both in female (p < 0.0001) and male (p < 0.0001) patients, however the slopes of the two regression lines were not significantly different (p = 0.7149), while the difference between the elevations was extremely significant (p < 0.0001) with a gap of 2.2 units between the two sexes. Finally, in a multivari- able linear regression analysis increased age and male sex were independently associated with higher QAlb in the overall study population (both p < 0.001) and after stratification by age and disease group. Conclusions: Accordingly, identification and validation of sex-targeted QAlb thresholds should be considered as a novel tool in an effort to achieve more precision in the medical approach

Autophagy and mitophagy biomarkers are reduced in sera of patients with Alzheimer's disease and mild cognitive impairment

Dementia is a neurocognitive disorder characterized by a progressive memory loss and impairment in cognitive and functional abilities. Autophagy and mitophagy are two important cellular processes by which the damaged intracellular components are degraded by lysosomes. To investigate the contribution of autophagy and mitophagy in degenerative diseases, we investigated the serum levels of specific autophagic markers (ATG5 protein) and mitophagic markers (Parkin protein) in a population of older patients by enzyme-linked immunosorbent assay. Two hundred elderly (≥65 years) outpatients were included in the study: 40 (20 F and 20 M) with mild-moderate late onset Alzheimer's disease (AD); 40 (20 F and 20 M) affected by vascular dementia (VAD); 40 with mild cognitive impairment (MCI); 40 (20 F and 20 M) with "mixed" dementia (MD); 40 subjects without signs of cognitive impairment were included as sex-matched controls. Our data indicated that, in serum samples, ATG5 and Parkin were both elevated in controls, and that VAD compared with AD, MCI and MD (all p < 0.01). Patients affected by AD, MD, and MCI showed significantly reduced circulating levels of both ATG5 and Parkin compared to healthy controls and VAD individuals, reflecting a significant down-regulation of autophagy and mitophagy pathways in these groups of patients. The measurement of serum levels of ATG5 and Parkin may represent an easily accessible diagnostic tool for the early monitoring of patients with cognitive decline

Multiplex Matrix Metalloproteinases Analysis in the Cerebrospinal Fluid Reveals Potential Specific Patterns in Multiple Sclerosis Patients

Background: Matrix metalloproteinases (MMPs) are pleiotropic enzymes involved in extracellular protein degradation and turnover. MMPs are implicated in the pathogenesis of many neurological diseases, including multiple sclerosis (MS).Objective: To search the level of MMPs in the cerebrospinal fluid (CSF) of MS patients and detect possible disease-specific patterns.Methods: CSF samples from 32 MS patients and, from 15 control subjects with other inflammatory neurological diseases (OIND) were analyzed. The Bio-Plex Pro Human MMP 9-Plex Panel (Bio-Rad) was used for the quantification of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, and MMP-13.Results: CSF MMP-1 and MMP-12 levels were significantly reduced in MS as compared with OIND. In MS patients' CSF: (i) MMP-1 levels were significantly higher in women vs. men; (ii) MMP-10 concentrations were higher in patients with CSF-restricted IgG oligoclonal bands, and (iii) MMP-7 levels were increased in patients with longer disease duration. In the OIND group MMP-7 and MMP-12 levels significantly and directly correlated with age.Conclusions: Our study contributes to investigating the role of MMPs in MS, with regard to CSF immunological features and disease duration. Sex-specific differences were also detected in MMPs CSF levels

Significant low prevalence of antibodies reacting with simian virus 40 mimotopes in serum samples from patients affected by inflammatory neurologic diseases, including multiple sclerosis

Many investigations were carried out on the association between viruses and multiple sclerosis (MS). Indeed, early studies reported the detections of neurotropic virus footprints in the CNS of patients with MS. In this study, sera from patients affected by MS, other inflammatory (OIND) and non-inflammatory neurologic diseases (NIND) were analyzed for antibodies against the polyomavirus, Simian Virus 40 (SV40). An indirect enzyme-linked immunosorbent assay (ELISA), with two synthetic peptides, which mimic SV40 antigens, was employed to detect specific antibodies in sera from patients affected by MS, OIND, NIND and healthy subjects (HS). Immunologic data indicate that in sera from MS patients antibodies against SV40 mimotopes are detectable with a low prevalence, 6%, whereas in HS of the same mean age, 40 yrs, the prevalence was 22%. The difference is statistically significant (P = 0.001). Significant is also the difference between MS vs. NIND patients (6% vs. 17%; P = 0.0254), whereas no significant difference was detected between MS vs OIND (6% vs 10%; P>0.05). The prevalence of SV40 antibodies in MS patients is 70% lower than that revealed in HS

Serum IgG against Simian Virus 40 antigens are hampered by high levels of sHLA-G in patients affected by inflammatory neurological diseases, as multiple sclerosis

Background: Many investigators detected the simian polyomavirus SV40 footprints in human brain tumors and neurologic diseases and recently it has been indicated that SV40 seems to be associated with multiple sclerosis (MS) disease. Interestingly, SV40 interacts with human leukocyte antigen (HLA) class I molecules for cell entry. HLA class I antigens, in particular non-classical HLA-G molecules, characterized by an immune-regulatory function, are involved in MS disease, and the levels of these molecules are modified according with the disease status. Objective: We investigated in serum samples, from Italian patients affected by MS, other inflammatory diseases (OIND), non-inflammatory neurological diseases (NIND) and healthy subjects (HS), SV40-antibody and soluble sHLA-G and the association between SV40-prevalence and sHLA-G levels. Methods: ELISA tests were used for SV40-antibodies detection and sHLA-G quantitation in serum samples. Results: The presence of SV40 antibodies was observed in 6 % of patients affected by MS (N = 4/63), 10 % of OIND (N = 8/77) and 15 % of NIND (N = 9/59), which is suggestive of a lower prevalence in respect to HS (22 %, N = 18/83). MS patients are characterized by higher sHLA-G serum levels (13.9 \ub1 0.9 ng/ml; mean \ub1 St. Error) in comparison with OIND (6.7 \ub1 0.8 ng/ml), NIND (2.9 \ub1 0.4 ng/ml) and HS (2.6 \ub1 0.7 ng/ml) subjects. Interestingly, we observed an inverse correlation between SV40 antibody prevalence and sHLA-G serum levels in MS patients. Conclusion: The data obtained showed a low prevalence of SV40 antibodies in MS patients. These results seems to be due to a generalized status of inability to counteract SV40 infection via antibody production. In particular, we hypothesize that SV40 immune-inhibitory direct effect and the presence of high levels of the immune-inhibitory HLA-G molecules could co-operate in impairing B lymphocyte activation towards SV40 specific peptides

Multiple sclerosis and HERV-W/MSRV: A multicentric study

We designed a large multicentric study to analyse the presence of MSRV particles in blood and CSF of a large cohort of patients and controls from different European areas. 149 MS patients and 153 neurological and healthy controls were selected from Sardinia, Spain, Northern-Italy and Sweden. To avoid biological and inter-assay variability MSRV was detected within a single laboratory through nested and real-time PCR assays specific for pol and env genes. MSRV detection in blood and CSF of MS patients and controls in populations of different ethnicity gave significant differences (p<0.05 compared to neurological controls and <0.001 compared to healthy controls). The presence and viral load of MSRV are significantly associated with MS as compared to neurological and healthy controls in all ethnic groups

Epstein-Barr virus and Multiple Sclerosis: in-depth analysis of the virus-specific antibody response at the time of diagnosis and during therapy

Introduction: Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) of unknown etiology. Seroepidemiological observations had associated MS to Epstein-Barr virus (EBV), a human !-herpesvirus with a widespread distribution in the human population. The first part of this study aimed to investigate this association by doing an in-depth analysis of the virus specific antibody response in a large cohort of MS patients and neurological controls. The second goal of the research was to verify the use of EBV-specific antibodies as biomarker for the response to treatment with disease modifying therapy. Methods: Serum and cerebrospinal fluid (CSF) concentrations, intrathecal synthesis, oligoclonal pattern and affinity distribution of EBV-specific IgG were determined in 100 multiple sclerosis relapsing-remitting (RRMS) patients and 200 age/sex matched controls with other inflammatory neurological disorders (OIND) and other non-inflammatory neurological disorders (NIND) at the time of diagnosis. Temporal fluctuations of EBV-specific IgG were measured in 20 RRMS patients treated with TYSABRI® for the first 15 months of therapy. Results: Levels of anti-EBNA-1 and anti-VCA IgG were different among RRMS, OIND and NIND in CSF (p&lt;0.0001 and p&lt;0.01, respectively) and serum (p&lt;0.001 and p&lt;0.05, respectively) samples. An intrathecal synthesis of anti-EBNA-1 IgG and anti-VCA IgG, as indicated by Antibody Index, was underrepresented in RRMS (6% and 2% respectively), in OIND (7% and 5%, respectively) and in NIND (2% and 1%, respectively). EBV-specific IgG oligoclonal bands (OCB) were detected in 24% RRMS patients and absent in controls. High-affinity antibodies were more frequent in RRMS than in NIND for CSF anti-EBNA-1 IgG (p&lt;0.05) and for serum anti-VCA IgG (p&lt;0.01) and in RRMS and OIND than in NIND for CSF anti-VCA IgG (p&lt;0.05). After treatment with 5M of NaSCN, EBV-specific IgG OCB had low affinity in all 24 RRMS patients analyzed. During 15 months of TYSABRI® therapy, temporal fluctuations of EBV-specific antibodies were not affected by drug treatment. This lack of statistical significance was also reflected in the comparison between patients who responded to treatment and patients who otherwise had relapsed during this period. Interpretation: Taken together these results do not support the potential role of an EBV persistent brain chronic infection in MS and suggest that an EBV-specific intrathecal oligoclonal IgG production can occur in a subset of MS patients as part of humoral polyreactivity driven by chronic brain inflammation. Moreover, our data argue against the use of EBV-specific antibodies as biomarker for monitoring therapeutic response to TYSABRI®

A Commentary on the Use of Epstein-Barr Virus Specific Antibodies as Biological Markers in Multiple Sclerosis

Multiple sclerosis (MS), a chronic demyelinating and neurodegenerative disease of the central nervous system (CNS), whose pathogenesis likely involves an interaction of environmental factors with a genetic predisposition. The hypothesis that Epstein-Barr virus (EBV), a ubiquitous human γ-herpesvirus may be a causal agent pivots on the evidence of EBV-specific antibodies high titers in MS patients as compared to controls, and on the observed direct association between such antibodies titers and disease activity. However, the literature on the possible etiological role of EBV is conflicting. This commentary aims to provide an overview on the use of EBV-specific antibodies as biomarkers in MS course