Determination of pentraxin 3 levels in cerebrospinal fluid during central nervous system infections.

Pentraxin 3 (PTX3) is an acute phase protein; its plasmatic levels significantly rise during severe infections. Data on PTX3 levels in cerebrospinal fluid (CSF) of patients with central nervous system (CNS) infections are lacking. We aimed (a) to assess the diagnostic potential of measuring CSF PTX3 levels in patients with CNS infections and (b) to establish CSF PTX3 cutoffs to distinguish between bacterial and aseptic meningoencephalitis (ROC curve). PTX3 levels were measured in CSF from 19 patients admitted to Trieste Hospital, Italy, with CNS infection. A diagnosis of bacterial infection and aseptic meningoencephalitis was made in 7 (37%) and 12 (63%) patients, respectively. Subjects with bacterial infections showed significantly higher PTX3 levels (13.5 vs 1.27 ng/mL in aseptic meningoencephalitis, p = 0.010). We identified two different CSF PTX3 levels cutoffs. (1) The best cutoff to maximise Youden's J was 9.6 ng/mL with a sensitivity, specificity, positive predictive value and negative predictive value (NPV) of 71.4%, 91.4%, 83.3%, 84.6%, respectively. (2) The cutoff with higher NPV (100%) was 3.6 ng/mL; a diagnosis of bacterial infections was obtained in 0% patients with CSF PTX3 levels < 3.6 ng/mL vs 58% of those with CSF PTX3 levels ≥ 3.6 ng/mL (p = 0.017). CSF PTX3 levels are higher in bacterial meningitis than aseptic meningoencephalitis. A cutoff of 3.6 ng/mL of CSF PTX3 has a high NPV and can be used to exclude bacterial CNS infections.

A Pilot Study Evaluating Cerebral Vasculitis in Kawasaki's Disease.

Cerebral vasculitis is thought to be a possible underlying mechanism of severe neurological complications of Kawasaki's disease (KD), such as cerebral infarct or aneurysm rupture. To evaluate the intracranial inflammatory response in patients with acute-stage KD, we measured the levels of cytokines (interleukin [IL]-6 and tumor necrosis factor [TNF]-α) and pentraxin-3 (PTX3) in the cerebrospinal fluid of patients with KD (n = 7) and compared the levels to those of the age- and sex-matched febrile control patients (bacterial meningitis [n = 5], enteroviral meningitis [n = 10], nonspecific viral illness without central nervous system involvement [n = 10]). PTX3 and TNF-α were rarely detected and only in trace concentration in KD, and the levels of IL-6 were not different from those of nonspecific viral illnesses. These mediators are not established biomarkers for cerebral vasculitis but might reflect vascular inflammation in various diseases including KD. Therefore, intracranial inflammation including vasculitis seems to be insignificant in our patients with KD. However, our results might be attributed to the fact that these patients lacked any clinical signs of cerebral or coronary vessel involvement. None of them underwent brain imaging. To clarify this issue, further studies involving patients with neurologic symptoms and proven involvement of cerebral vessels are needed.

Cerebrospinal fluid pentraxin 3 and CD40 ligand in anti-N-menthyl-d-aspartate receptor encephalitis.

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder of the central nervous system whose pathogenesis involves interleukin (IL)-6 and IL-17A. We examined the correlations between CSF concentrations of the acute-phase protein pentraxin 3 (PTX3), the chronic inflammatory mediator CD40L, IL-6, and IL-17A in anti-NMDAR encephalitis, and the impact on clinical outcome. PTX3, CD40L, IL-6, and IL-17A were significantly higher in the CSF of patients with anti-NMDAR encephalitis than in controls. Within the former, PTX3 levels correlated positively with IL-6 and the mRS, and CD40L levels with IL-17A and the mRS. Higher PTX3 and CD40L levels may reflect the underlying neuroinflammation.

Pentraxin-3 is upregulated in the central nervous system during MS and EAE, but does not modulate experimental neurological disease.

Pentraxin-3 (PTX3), an acute-phase protein released during inflammation, aids phagocytic clearance of pathogens and apoptotic cells, and plays diverse immunoregulatory roles in tissue injury. In neuroinflammatory diseases, like MS, resident microglia could become activated by endogenous agonists for Toll like receptors (TLRs). Previously we showed a strong TLR2-mediated induction of PTX3 in cultured human microglia and macrophages by HspB5, which accumulates in glia during MS. Given the anti-inflammatory effects of HspB5, we examined the contribution of PTX3 to these effects in MS and its animal model EAE. Our data indicate that TLR engagement effectively induces PTX3 expression in human microglia, and that such expression is readily detectable in MS lesions. Enhanced PTX3 expression is prominently expressed in microglia in preactive MS lesions, and in microglia/macrophages engaged in myelin phagocytosis in actively demyelinating lesions. Yet, we did not detect PTX3 in cerebrospinal fluid of MS patients. PTX3 expression is also elevated in spinal cords during chronic relapsing EAE in Biozzi ABH mice, but the EAE severity and time course in PTX3-deficient mice did not differ from WT mice. Moreover, systemic PTX3 administration did not alter the disease onset or severity. Our findings reveal local functions of PTX3 during neuroinflammation in facilitating myelin phagocytosis, but do not point to a role for PTX3 in controlling the development of autoimmune neuroinflammation.

Cerebrospinal fluid pentraxin 3 early after subarachnoid hemorrhage is associated with vasospasm.

PURPOSE: To investigate plasma and cerebrospinal fluid (CSF) concentrations of pentraxin 3 (PTX3), a prototypic long pentraxin protein induced by proinflammatory signals, in subarachnoid hemorrhage (SAH), and its relation with SAH-associated vasospasm. METHODS: Serial plasma and CSF samples were collected from 38 consecutive SAH patients admitted to the Neurosurgical Intensive Care. PTX3 concentrations were analyzed in relation to clinical status and clinical vasospasm (defined as neuro-worsening and angiographic confirmation of vessel narrowing). Since neutrophils are an important source of preformed PTX3, myeloperoxidase (MPO) in CSF was measured to assess the correlation with CSF PTX3 and establish whether blood contamination was the determinant of PTX3 increase. RESULTS: PTX3 was elevated in all SAH patients both in plasma and CSF. Acute peak (first 48 h after SAH) CSF PTX3 was significantly higher in patients who later developed vasospasm [median 13.6 (range 2.3-51.9) ng/ml] compared to those who did not [3.2 (0.1-50.5) ng/ml, p = 0.03]. The temporal pattern of CSF PTX3 in patients with vasospasm was triphasic with a peak during the first 48 h after SAH, a subsequent decrease in the following 48-96 h and a secondary significant increase with the occurrence of vasospasm. A loose correlation between CSF PTX3 and MPO was observed (r(2) = 0.13), indicating that following SAH there is a brain production of PTX3. CONCLUSIONS: Acute increased concentrations of PTX3 in CSF but not in plasma are related to the occurrence of vasospasm, indicating that measurement of CSF PTX3 associated with the clinical evaluation can improve early diagnosis of this complication.

Evaluation of intrathecal serum amyloid P (SAP) and C-reactive protein (CRP) synthesis in Alzheimer's disease with the use of index values.

Serum amyloid P (SAP) and C-reactive protein (CRP) are proteins involved in innate immunity. The expression of SAP and CRP is increased in Alzheimer's disease (AD) brain tissue, compared to healthy controls. Although both proteins are found in cerebrospinal fluid (CSF), their origin is unclear. We investigated if increased local production of SAP and CRP in AD brain results in higher levels in CSF with the use of index values. To study this, SAP, CRP, and albumin levels were determined in CSF and serum samples of 30 control (65 ± 11 years; 57% female) and 140 AD subjects (65 ± 9 years; 53% female). To correct for inter-individual differences in protein diffusion from blood to CSF, quotients (Q =CSF/serum) of SAP, CRP, and albumin and index values (Qprotein/Qalb) were calculated. The results showed no significant differences in SAP and CRP index values between control and AD subjects, although eight percent of individual AD patients showed evidence of intrathecal SAP or CRP production using the Reiber hyperbolic model. Interestingly, the SAP index value was much lower than expected, based on its molecular size. In conclusion, these data suggest that local production of SAP and CRP in the AD brain does not substantially contribute to the CSF levels.

Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component.

New therapeutic approaches in Alzheimer's disease are urgently needed. The normal plasma protein, serum amyloid P component (SAP), is always present in cerebrospinal fluid (CSF) and in the pathognomonic lesions of Alzheimer's disease, cerebrovascular and intracerebral Abeta amyloid plaques and neurofibrillary tangles, as a result of its binding to amyloid fibrils and to paired helical filaments, respectively. SAP itself may also be directly neurocytotoxic. Here, in this unique study in Alzheimer's disease of the bis(d-proline) compound, (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), we observed depletion of circulating SAP and also remarkable, almost complete, disappearance of SAP from the CSF. We demonstrate that SAP depletion in vivo is caused by CPHPC cross-linking pairs of SAP molecules in solution to form complexes that are immediately cleared from the plasma. We have also solved the structure of SAP complexed with phosphothreonine, its likely ligand on hyperphosphorylated tau protein. These results support further clinical study of SAP depletion in Alzheimer's disease and potentially other neurodegenerative diseases.

Serum amyloid p component as a biomarker in mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Serum amyloid P component (SAP), present in amyloid-beta (Abeta) plaques in Alzheimer's disease (AD), may protect Abeta deposits against proteolysis, thereby promoting plaque formation. The aim was to investigate if SAP levels in cerebrospinal fluid (CSF) and serum can be used to discriminate controls, AD and mild cognitive impairment (MCI) patients, and to identify incipient AD among MCI patients. METHODS: SAP levels in CSF and serum were determined in 30 controls, 67 MCI and 144 AD patients. At follow-up, 39 MCI patients had progressed to dementia, while 25 had remained stable (mean follow-up time: 2.6 +/- 1.0 and 2.1 +/- 0.8 years). RESULTS: Cross-sectionally no differences were found in SAP levels in CSF and serum between the groups. MCI patients that had progressed to dementia at follow-up had lower CSF SAP levels (13 microgram/l, range 3.3-199.3 microgram/l) than MCI nonprogressors (20.2 microgram/l, range 7.0-127.7 microgram/l; p < 0.05) [corrected]. A low CSF SAP level was associated with a 2-fold increased risk of progression to AD (hazard ratio = 2.2; 95% confidence interval = 0.9-5.4). CONCLUSION: Our data suggest that measurement of CSF SAP levels can aid in the identification of incipient AD among MCI patients.

CSF markers related to pathogenetic mechanisms in Alzheimer's disease.

Serum amyloid P component (SAP) and complement C1q are found highly co-localized with extracellular fibrillar amyloidbeta (Abeta) deposits in Alzheimer's disease (AD) brain. Conflicting data were reported earlier about the cerebrospinal fluid (CSF) levels of SAP and C1q in AD compared to controls. The objective of the present study was to compare the levels of Abeta(1-42), tau, C1q and SAP in CSF of a well characterized group of AD patients and controls, and to assess the association with dementia severity. Significantly decreased CSF levels of Abeta(1-42) were observed in the AD group (480 +/- 104 ng/L) as compared to controls (1,040 +/- 213 ng/L), whereas tau levels were significantly higher in patients with AD (618 +/- 292 ng/L) than in controls (277 +/- 136 ng/L). Combining the results of Abeta(1-42) and tau measurements resulted in a clear separation between the AD group and the controls. No significant differences in CSF levels of SAP and C1q were observed between the well characterized AD patients and non demented control group. Furthermore, we could not demonstrate a correlation between SAP and C1q CSF levels and the severity of the disease, expressed in Mini-Mental State Examination (MMSE) scores. Therefore, in our opinion these factors can be excluded from the list of potentially interesting biomarkers for AD diagnosis and progression.

Assessment of cerebrospinal fluid levels of serum amyloid P component in patients with Alzheimer's disease.

Serum amyloid P component (SAP) is a normal plasma constituent that is observed both in senile plaque and in neurofibrillary tangle in brains of patients with Alzheimer's disease (AD). In this study, we evaluated the SAP levels in cerebrospinal fluid (CSF) of 72 patients with AD, 11 frontotemporal dementia and nine normal control subjects. There was no significant difference in the SAP levels between the AD group and other groups. However, among AD patients, cognitive function was rated using the Mini-Mental State Examination and was correlated with the SAP level (R = 0.38, P < 0.05). Our results suggest that measurement of the SAP levels in CSF can be useful for assessing the degree of cognitive impairment in AD patients.

Concentration of serum amyloid P component in the CSF as a possible marker of cerebral amyloid deposits in Alzheimer's disease.

Serum amyloid P component (SAP) is a normal plasma protein produced in the liver and co-deposited with amyloid fibrils in all types of amyloidosis, including cerebral beta-protein amyloid deposits associated with Alzheimer's disease (AD). We have measured its concentration and those of alpha 2-macroglobulin, IgG and albumin in the CSF of 51 patients with AD and 50 healthy and disease control subjects. The mean levels of SAP were 12.8 ng/ml in AD and 8.5 ng/ml in controls (P < 0.0125); there was no difference in the levels of the other proteins studied. The observed concentrations of SAP were much lower than expected for a protein of molecular weight 254620. The difference between AD and controls suggests that the concentration of SAP in the CSF may be affected by the presence of cerebral amyloidosis.