Lower Serum Antibodies Against Tau Protein and Heavy Neurofilament in Alzheimer's Disease.

BACKGROUND: Unlike antibodies against amyloid-ß, little is known about serum antibodies to neuron-specific cytoskeletal proteins in patients with Alzheimer's disease (AD). OBJECTIVE: We aimed to study IgG autoantibodies against tau protein, light (NFL) and heavy subunits (NFH) of neurofilaments in serum of AD patients and elderly controls and to explore the evolution of antineurocytoskeletal antibody levels over time. METHODS: Antibodies against three targets (tau, NFL, and NFH) were measured using ELISA in 100 serum samples from 51 cognitively normal elderly controls and 49 patients with AD. Our primary cross-sectional design was further extended to monitor fluctuations over 1-2 years in a subset of individuals. RESULTS: The AD patients had lower levels of anti-tau antibodies (p = 0.03) and even lower anti-NFH antibodies (p = 0.005) than those in the control group at baseline. On the contrary, anti-NFL antibodies or total IgG concentrations in serum did not differ. All three antibodies remained stable in both groups except for a selective and significant anti-tau decline in AD patients (p = 0.03). CONCLUSIONS: The different responses to these antigens suggest some antibody selectivity in AD. The significant decline was observed for only serum anti-tau antibodies in AD patients over time and it corresponds to lower anti-tau levels in these patients. Our findings indicate a special feature of disease-relevant antigens and humoral autoimmunity in AD.

Neurofilaments and tau proteins in cerebrospinal fluid and serum in dementias and neuroinflammation.

AIMS: The aim of this study was to evaluate the diagnostic potential of cerebrospinal fluid (CSF) and serum levels of neurocytoskeletal proteins and their ratios for the diagnosis of dementias and to assess the differences in neurocytoskeletal proteins between neurodegeneration and neuroinflammation. METHODS: CSF and serum levels of neurofilament light subunits (NFL) and neurofilament heavy subunits (NFH) as well as CSF levels of total tau (t-tau) and phosphorylated tau (p-tau) proteins were determined using ELISA in 20 Alzheimer's disease patients (AD group), 13 patients with other dementias (OD group), 17 patients with inflammatory aseptic neuro-infections (IP), and 20 aged-matched cognitively normal elderly persons (NC group). RESULTS: The ratio CSF p-tau/t-tau was significantly higher in the NC group than that in the AD or OD groups (P<0.0005 for each group). The CSF NFH/p-tau and CSF NFL/p-tau ratios were significantly lower in AD patients than OD patients (P≤0.003). Serum and CSF NFL and CSF NFH levels were significantly higher in OD patients than AD patients (P≤0.03). The lowest values of the CSF NFL/NFH ratio were found in the IP group and they significantly differed from those in normal controls (P<0.0001) and any dementia group (IP vs. AD P<0.0001; IP vs. OD P=0.03). CONCLUSION: CSF tau proteins and their index differentiated between AD or OD patients and cognitively normal subjects, while CSF levels of neurofilaments expressed as their index seem to contribute to the discrimination between patients with neuroinflammation and normal controls or AD patients.

Serum and cerebrospinal fluid light neurofilaments and antibodies against them in clinically isolated syndrome and multiple sclerosis.

A release of light neurofilament subunits (NFL) into cerebrospinal fluid (CSF) and serum in multiple sclerosis (MS) may induce an immune response. We examined CSF and serum NFL levels and IgG antibodies against NFL in 19 patients with a clinically isolated syndrome (CIS) early converted into MS, 20 CIS-non-converters, 23 MS patients and 32 controls. CSF NFL levels were significantly higher in all patient groups. The highest CSF or intrathecally (IT) synthesized anti-NFL antibodies and CSF/serum ratios of anti-NFL antibodies were observed in CIS-converters. CSF NFL and CSF or IT anti-NFL antibodies could be surrogate biomarkers of axonal injury in early MS.

Serum and cerebrospinal fluid heavy neurofilaments and antibodies against them in early multiple sclerosis.

Heavy neurofilaments (NFH) released from neurons during axonal injury induce a humoral immune response. We measured CSF and serum levels of NFH proteins and anti-NFH IgG antibodies in 19 patients with clinically isolated syndrome (CIS) converting to multiple sclerosis, in 20 stable CIS patients, 23 patients with multiple sclerosis (MS) and 32 control subjects using ELISA. CSF and intrathecal levels and CSF/serum ratios of anti-NFH antibodies were increased in the CIS patients early developing MS while NFH protein concentrations were similar among the groups. Changes associated with NFH are more pronounced for antibodies than for protein itself and may aid in prediction of CIS patients.

Patients with Alzheimer disease have elevated intrathecal synthesis of antibodies against tau protein and heavy neurofilament.

The role of humoral immunity related to neuron- and disease-specific cytoskeletal proteins patients with Alzheimer disease (AD) is unknown. We measured antibodies against tau protein, light and heavy (NFH) neurofilaments using ELISA in 80 paired serum and cerebrospinal fluid (CSF) samples from patients with AD, with other dementias (OD), with neuro-inflammatory diseases (IC) and 25 controls (NC). We estimated intrathecal synthesis according to the formula (CSF/serum anti-neurocytoskeletal IgG)/(CSF/serum total IgG). AD patients had significantly higher intrathecal anti-tau and anti-NFH antibodies than the other groups. These innovative findings may hint at specific alterations in humoral anti-neurocytoskeletal immunity and selectivity in AD, which could have diagnostic and immunotherapeutic implications.

Increased intrathecal high-avidity anti-tau antibodies in patients with multiple sclerosis.

BACKGROUND: Antibodies against tau protein indicate an interaction between the immune system and the neurocytoskeleton and therefore may reflect axonal injury in multiple sclerosis (MS). METHODOLOGY/PRINCIPAL FINDINGS: The levels and avidities of anti-tau IgG antibodies were measured using ELISA in paired cerebrospinal fluid (CSF) and serum samples obtained from 49 MS patients and 47 controls. Anti-tau antibodies were significantly elevated intrathecally (p<0.0001) in the MS group. The CSF anti-tau antibody levels were lower in MS patients receiving therapy than those without treatment (p<0.05). The avidities of anti-tau antibodies were higher in the CSF than in the serum (MS group p<0.0001; controls p<0.005). Anti-tau avidities in the CSF were elevated in MS patients in comparison with controls (p<0.05), but not in serum. CONCLUSIONS: MS patients have higher levels of intrathecal anti-tau antibodies. Anti-tau antibodies have different avidities in different compartments with the highest values in the CSF of MS patients.

Association of pregnancy-associated plasma protein A polymorphism with preeclampsia - a pilot study.

OBJECTIVES: The aim of the study was to investigate genetic and biochemical background of PAPP-A (pregnancy-associated plasma protein A) in patients with risk pregnancies. DESIGN AND METHODS: Five PAPP-A gene polymorphisms and PAPP-A maternal serum levels were studied together in 165 women in third trimester pregnancies complicated with threatening preterm labor (n=98), preeclampsia (n=35), intrauterine growth restriction (n=34) and ICP (intrahepatic cholestasis of pregnancy) (n=15). 114 healthy pregnant women served as controls. RESULTS: Preeclamptic patients had significantly higher frequency of TT genotype of Cys327Cys polymorphism compared to controls (p<0.01). Patients with ICP had increased serum levels of PAPP-A compared to controls and correlation analysis showed significant relationship between PAPP-A and CRP (C-reactive protein) in the patients with intrauterine growth restriction (r=0.49, p=0.007). CONCLUSION: Our study indicates the association of TT genotype of Cys327Cys polymorphism of the PAPP-A gene with preeclampsia. However, further study with larger groups of preeclamptic patients is needed to confirm our results.

Biochemical oxidative stress-related markers in patients with obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is a condition contributing to oxidative stress. The aim of this study was to ascertain if there is any connection between OSA and novel oxidative stress-related markers. Matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), high sensitive C-reactive protein (hsCRP), pregnancy-associated plasma protein-A (PAPP-A), soluble receptors for advanced glycation end-products (sRAGE), zinc (Zn) and copper (Cu) were measured. Further biochemical markers were evaluated. MATERIAL/METHODS: Fifty-one men suspected for OSA indicated for night polygraphy were included. Apnea/hypopnea index (AHI), oxygen desaturation index (ODI), mean blood hemoglobin oxygen saturation (SpO2) and time of blood hemoglobin oxygen saturation below 90% (SpO2 <90%) were measured. Morning venous blood samples were taken. RESULTS: For body mass index (BMI) we found strong positive correlation with levels of Cu, MMP-9, hsCRP and fibrinogen, and negative correlation with sRAGE. Concerning ventilation parameters, we found positive correlation of ODI and SpO2 <90% with markers MMP-9 and hsCRP. sRAGE level correlated with AHI and ODI negatively. SpO2 correlated negatively with Cu, MMP-9, hsCRP and fibrinogen. There was no correlation between ventilation parameters and markers MMP-2, PAPP-A and Zn. Compared to severity of OSA, there was significant difference in levels of hsCRP and Cu between patients with AHI ≤5 and AHI ≥30 independent of BMI. CONCLUSIONS: MMP-9, hsCRP, sRAGE and Cu seem to be strong predictors of oxidative stress in OSA patients. The strong correlation between oxidative stress-related markers and OSA is elucidated by connection of these to BMI, which is probably a primary condition of oxidative stress, but OSA is an additive condition.

Low maternal serum matrix metalloproteinase (MMP)-2 concentrations are associated with preterm labor and fetal inflammatory response.

OBJECTIVES: to assess the relationship between maternal and umbilical serum concentrations of matrix metalloproteinases (MMP)-2,8,9, the soluble receptor for advanced glycation end products (sRAGE) and IL-10 and premature delivery and fetal inflammation. METHODS: maternal serum levels of MMPs, sRAGE, IL-10 and C-reactive protein (CRP) were determined in 67 women with preterm labor and in 38 healthy pregnant women of similar gestational age (GA). In the group with preterm labor we also determined umbilical concentrations of MMPs, IL-6 and sRAGE. The group with preterm labor was additionally divided based on the presence of funisitis and elevations of fetal umbilical IL-6 concentrations. RESULTS: maternal serum levels of MMP-2 and sRAGE were significantly lower in women with preterm labor compared to women with normal pregnancy. Additionally, within the group of women with preterm labor, maternal serum MMP-2 concentrations were significantly lower in the subgroup with funisitis and in the subgroup with elevated umbilical concentration of IL-6. CONCLUSION: our results demonstrate significantly different serum concentrations of MMP-2 and sRAGE in women with preterm labor compared to healthy pregnant patients of the same GA.