Sara Haghighi

Reduced cerebrospinal fluid BACE1 activity in multiple sclerosis.

Background Cell and animal experiments have shown that β-site APP-cleaving enzyme 1 (BACE1) may be involved in myelination. Objective Here, we assess the association of cerebrospinal fluid (CSF) BACE1 activity with multiple sclerosis (MS). Methods BACE1 activity and levels of secreted amyloid precursor protein (APP) and amyloid-β (Aβ) isoforms were analyzed in CSF from 100 patients with MS and 114 neurologically healthy controls. Patients with systemic lupus erythematosus (SLE), 26 with and 41 without cerebral engagement, were also included to enable comparisons with regards to another autoimmune disease. A subset of patients with MS and controls underwent a second lumbar puncture after 10 years. Results MS patients had lower CSF BACE1 activity than controls (P = 0.03) and patients with cerebral SLE (P < 0.001). Patients with cerebral SLE had higher BACE1 activity than any other group (P < 0.05 for all comparisons). BACE1 activity correlated with the different amyloid markers in all study groups. BACE1 activity decreased over 10 years in the MS group (P = 0.039) and correlated weakly with clinical disease severity scores in an inverse manner. Conclusions These results suggest an involvement of BACE1 in the MS disease process.

Efficacy and Safety of the Dopaminergic Stabilizer Pridopidine (ACR16) in Patients With Huntington's Disease.

Objectives:To evaluate the efficacy and safety of the dopaminergic stabilizer pridopidine (ACR16) in patients with Huntingtons disease (HD). Methods:In a randomized, double-blind, placebo-controlled, 4-week trial, patients with HD received pridopidine (50 mg/d, n = 28) or placebo (n = 30). The primary outcome measure was the change from baseline in weighted cognitive score, assessed by cognitive tests (Symbol Digit Modalities, verbal fluency, and Stroop tests). Secondary outcome measures included changes in the Unified Huntingtons Disease Rating Scale, Hospital Anxiety and Depression Scale, Leeds Sleep Evaluation Questionnaire, Reitan Trail-Making Test A, and Clinical Global Impression of Change. Safety assessments were also performed. Results:There was no significant difference between pridopidine and placebo in the change from baseline of the weighted cognitive score. However, secondary measures such as affective symptoms showed trends toward improvement, and there was significant improvement in voluntary motor symptoms compared with placebo (P < 0.05). Pridopidine was well tolerated, with a safety profile similar to placebo. Conclusions:Pridopidine shows promise as a treatment for some of the symptoms of HD. In this small-scale study, the most notable effect was improvement in voluntary motor symptoms. Larger, longer-term trials are warranted.

IL-6 and CCL2 levels in CSF are associated with the clinical course of MS : Implications for their possible immunopathogenic roles

Biological markers would provide valuable tools for tracking disease activity, immunopathological processes or therapeutic efficacy in MS. In this study we analysed a panel of Th(1)/Th(2) cytokines and the chemokine CCL2 in serum and CSF from MS patients and healthy controls. Increased levels of IL-6 (p<0.05) and decreased levels of CCL2 (p<0.001), with the lowest levels during acute relapses, was found in CSF from patients with relapsing-remitting MS. CSF levels of CCL2 correlated with indices for intrathecal IgG production and the CSF level of the neurofilament light protein, a marker for axonal damage, indicating a immunopathogenic role for CCL2.

Relapses in multiple sclerosis are associated with increased CD8+ T-cell mediated cytotoxicity in CSF

MS is thought to be mediated by CD4(+) T-helper cells. To investigate the importance of CD8(+) cytotoxic T-cells in MS we analyzed peripheral blood T-cells by DNA microarray, and plasma and CSF levels of granzymes from MS patients and controls. Cytotoxic gene expression was decreased in peripheral T-cells from RRMS patients whereas plasma levels of granzymes were unchanged. However, granzyme levels were elevated in the CSF of RRMS patients at relapse compared with controls and remission. Thus, CD8+ T-cell-mediated cytotoxicity is confined to the CSF/CNS compartment in RRMS patients and may be involved in the immunopathogenesis of clinical relapses.

Cystatin C in cerebrospinal fluid and multiple sclerosis.

A recent study using surface‐enhanced laser desorption/ionization time‐of‐flight analysis of cerebrospinal fluid identified a 12.5kDa truncated isoform of cystatin C (CysC) as a specific biomarker for multiple sclerosis (MS).

Elevated cerebrospinal fluid F2-isoprostane levels indicating oxidative stress in healthy siblings of multiple sclerosis patients.

Lipid peroxidation has been implicated in the pathogenesis of multiple sclerosis (MS). Isoprostanes, isomers of prostaglandins, are produced by free radical-mediated peroxidation of fatty acids in vivo and can be quantified in biological fluids. This study examines the levels of cerebrospinal fluid (CSF) F2-isoprostanes (F2-iPs) in MS patients (n=46), their healthy siblings (n=46) and unrelated controls (n=50). The median CSF F2-iP concentration (range) was significantly higher in siblings of MS patients, as compared to healthy controls (40.0 [7.1-68.7] and 29.1 [6.4-60.3] pg/mL, respectively, p=0.031). MS patients demonstrated F2-iP levels intermediate between siblings and controls. F2-iP levels in MS patients and siblings correlated significantly (R=0.360, p=0.012). These results suggest that siblings of MS patients have an increased oxidative stress response to environmental and/or genetic factors that may be involved in MS pathogenesis.

Incidence of CSF abnormalities in siblings of multiple sclerosis patients and unrelated controls.

Abstract We found that 19% (9/47) of healthy siblings of patients with clinically definite multiple sclerosis had an intrathecal immunological reaction with two or more 2 CSF-enriched oligoclonal bands (OCBs), in contrast to (4%) (2/50) unrelated healthy controls. Furthermore, in this group of nine healthy sibs the measles CSF IgG antibody titers were higher than that of the other sibs and that of controls. There were also differences in the serum titers for measles IgG antibody, which were higher in the group of all healthy sibs than in healthy volunteers, and (as with CSF titers) higher in the subgroup of healthy sibs with two or more 2 CSF-enriched OCBs than the other sibs. Thus a significant proportion of healthy siblings to MS patients have a partially hyperimmune condition similar to that occurring in MS, which in 19% manifested itself as an OCB reaction, in 9% as increased CSF measles IgG antibody titers, and in 21% as increased serum measles IgG antibody titers, these phenomena tending to occur in the same individuals. This condition is characterized by CSF-enriched OCBs with undefined specificity, although some increased antiviral reactivity is found both in the serum and CSF. While it needs further characterization, a genetic trait interacting with common infections is suggested. The recurrence risk of this condition is approximately five times higher than the 3–4% recurrence risk for manifest MS reported for sibs.

Cerebrospinal fluid markers in MS patients and their healthy siblings

In a previous study we found that nine of 47 siblings to multiple sclerosis (MS) patients with a normal neurological examination carry an intrathecal oligoclonal immunopathy with limited specificity, a condition we termed MS immunopathic trait. The purpose of this study is to further characterize the MS immunopathic trait phenotype. We found that the neurofilament light protein (NFL) and glial fibrillary acidic protein (GFAp) concentrations were increased in the group of patients with clinically definite MS (n = 47) in latent or slowly progressive phases. There was no increase in GFAp and NFL in cerebrospinal fluid in the healthy siblings of MS patients (n = 47), nor in the subgroup of these siblings with MS immunopathic trait (n = 9) compared with a group of healthy control subjects (n = 50). Thus, there was no indication of presymptomatic CNS parenchymal involvement in MS immunopathic trait.

Cerebrospinal fluid concentrations of peptides derived from chromogranin B and secretogranin II are decreased in multiple sclerosis

Novel biomarkers for multiple sclerosis (MS) could improve diagnosis and provide clues to pathogenesis. In this study surface‐enhanced laser desorption/ionization time‐of‐flight mass spectrometry was used to analyze protein expression in CSF from 46 MS patients, 46 healthy siblings to the patients, and 50 unrelated healthy controls. Twenty‐four proteins in the mass range 2–10 kDa were expressed at significantly different levels (p < 0.01) in a robust manner when comparing the three groups. Identities of three proteins were determined using biochemical purification followed by tandem mass spectrometric analysis. Immunoprecipitation experiments confirmed the identities for two peptides derived from chromogranin B (m/z 6252) and from secretogranin II (m/z 3679). These peptides were all decreased in MS when compared with siblings or controls. Radioimmunoassays specific for each peptide confirmed these differences. The lowered concentrations did not correlate to the axonal damage marker neurofilament light protein and may thus reflect functional changes rather than neurodegeneration. Further studies will investigate the involvement of these peptides in MS pathogenesis.

A linkage study in two families with multiple sclerosis and healthy members with oligoclonal CSF immunopathy

We studied two extended families in which not only multiple sclerosis (MS) segregates, but also approximately 18% of the cerebrospinal fluid (CSF) investigated blood relatives have ‘MS immunopathic trait’, an oligoclonal CSF immunopathy similar to that seen in MS, but with no neurological symptoms. Both families fit a genetic model for autosomal dominant inheritance for MS immunopathic trait, although with reduced penetrance in family A. In order to identify genetic factors of importance for the development of MS immunopathic trait, we performed a genome scan using the CHLC/Weber Screening Set (ver 6A), with 285 successful markers, to test the hypothesis that a single gene is causing the MS immunopathic trait in these families. Using a parametric method, we identified regions with suggestive linkage at chromosome 6q12 with a LOD-score of 2.4, putative linkage with LOD-score 1.5 at chromosome 6p21 (HLA region), putative linkage at chromosome 12q24 with a LOD-score of 1.7 and suggestive linkage at chromosome 19q13.2 with a LOD-score of 1.8. The LOD-score at chromosome 19q13.2 increased to 2.2 when only family A was analysed. In family A, all MS patients and two of five individuals with MS immunopathic trait had HLA DRB1*(15) and in family B, all blood relatives had the rare HLA type DRB1*0103, which is associated with other autoimmune diseases. We suggest that DRB1*0103 is a necessary but not sufficient condition for the susceptibility for MS immunopathic trait in this family.