Acute Phase Proteins in Cerebrospinal Fluid from Dogs with Naturally-Occurring Spinal Cord Injury.

Spinal cord injury (SCI) affects thousands of people each year and there are no treatments that dramatically improve clinical outcome. Canine intervertebral disc herniation is a naturally-occurring SCI that has similarities to human injury and can be used as a translational model for evaluating therapeutic interventions. Here, we characterized cerebrospinal fluid (CSF) acute phase proteins (APPs) that have altered expression across a spectrum of neurological disorders, using this canine model system. The concentrations of C-reactive protein (CRP), haptoglobin (Hp), alpha-1-glycoprotein, and serum amyloid A were determined in the CSF of 42 acutely injured dogs, compared with 21 healthy control dogs. Concentrations of APPs also were examined with respect to initial injury severity and motor outcome 42 d post-injury. Hp concentration was significantly higher (p<0.0001) in the CSF of affected dogs, compared with healthy control dogs. Additionally, the concentrations of CRP and Hp were significantly (p=0.0001 and p=0.0079, respectively) and positively associated with CSF total protein concentration. The concentrations of CRP and Hp were significantly higher (p=0.0071 and p=0.0197, respectively) in dogs with severe injury, compared with those with mild-to-moderate SCI, but there was no significant correlation between assessed CSF APP concentrations and 42 d motor outcome. This study demonstrated that CSF APPs were dysregulated in dogs with naturally-occurring SCI and could be used as markers for SCI severity. As Hp was increased following severe SCI and is neuroprotective across a number of model systems, it may represent a viable therapeutic target.

Acute inflammatory biomarkers in cerebrospinal fluid as indicators of blood cerebrospinal fluid barrier damage in Japanese subjects with infectious meningitis.

BACKGROUND: The blood-cerebrospinal fluid barrier (BCB) has selectivity for protein components with different molecular weights. Protein components in the cerebrospinal fluid (CSF) change when the BCB is damaged. We calculated the alpha2 macroglobulin (alpha2M) index as an indicator of BCB permeability from the point of view of molecular weight and evaluated the relationship between the alpha2M index and CSF concentrations of the inflammatory biomarkers interleukin-6 (IL-6), C-reactive protein (CRP), and serum amyloid A (SAA) in Japanese subjects with infectious meningitis, in order to determine the clinical significance of those inflammatory biomarkers in CSF. METHODS: IL-6, CRP, and SAA levels in CSF and serum were measured using various methods. The alpha2M index was calculated as the ratio of alpha2M (CSF/serum) to albumin (CSF/serum). RESULTS: CSF IL-6 levels were higher than serum IL-6 levels in 16 patients with infectious meningitis. The difference in CSF IL-6 and CRP levels between mycotic or bacterial meningitis cases and healthy controls and in CSF SAA levels between all infectious meningitis cases and healthy controls were significant. There was a significant positive correlation between CSF levels of CRP or SAA and alpha2M indices. CONCLUSIONS: Markedly increased levels of IL-6 in the CSF of patients with infectious meningitis may reflect the degree of intrathecal inflammation. On the other hand, increased CSF levels of CRP in patients with infectious meningitis, particularly mycotic or bacterial meningitis, and SAA in patients with all infectious meningitis may reflect the degree of damage to the BCB.

Platelets provide human tissue to unravel pathogenic mechanisms of Alzheimer disease.

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterised by a progressive cognitive and memory decline. From a neuropathological point of view, Alzheimer disease is defined by the presence of characteristic lesions, i.e. mature senile plaques, neurofibrillary tangles and amyloid angiopathy. In particular, accumulation of the amyloid beta-peptide in the brain parenchyma and vasculature is an invariant event in the pathogenesis of both sporadic and familial Alzheimer cases. Amyloid beta-peptide originates from a larger precursor, the Amyloid Precursor Protein (APP) ubiquitously expressed. Among the different peripheral cells expressing APP forms, platelets are particularly interesting since they show concentrations of its isoforms equivalent to those found in brain. Moreover, a number of laboratories independently described alterations in APP metabolism/concentration in platelets of Alzheimer patients when compared to control subjects matched for demographic characteristics. These observations defined the frame of our work aimed to investigate if a correlation between levels of platelet APP forms and Alzheimer disease could be detected. We have reported that patients affected by Alzheimer disease show a differential level of platelet APP forms. This observation has several implications: APP processing abnormalities, believed to be a very early change in Alzheimer disease in neuronal compartment, does occur in extraneuronal tissues, such as platelets, thus suggesting that Alzheimer disease is a systemic disorder; further, our data strongly indicate that a differential level of platelet APP forms can be considered a potential peripheral marker of Alzheimer disease allowing for discrimination between Alzheimer and other types of dementia with good sensitivity and specificity.

Levels of three inflammation markers, C-reactive protein, serum amyloid A protein and procalcitonin, in the serum and cerebrospinal fluid of patients with meningitis.

The levels of C-reactive protein (CRP) and serum amyloid A protein (SAA) in blood are increased in patients with inflammatory diseases as acute phase proteins. Most of the presently used indicators of inflammation, such as body temperature, white cell count, erythrocyte sedimentation rate or CRP, are non-specific parameters. In contrast, procalcitonin (PCT) has been reported to be selectively induced by severe bacterial infection during the systemic inflammatory response syndrome (SIRS), and also in sepsis or multiorgan dysfunction syndrome. PCT expression is only slightly induced, if at all, by viral infections, autoimmune disorders, neoplastic diseases and trauma of surgical intervention. We measured the concentrations of CRP, SAA and PCT in the sera and cerebrospinal fluid (CSF) of 30 patients with bacterial, viral, or mycotic meningitis, and 12 patients with a noninflammatory central nervous system disease as controls. An extremely high CRP level in CSF of above 100 microg/L was seen in all seven bacterial meningitis patients and in only 10% of the viral meningitis patients. A high SAA level in CSF of greater than 10 microg/L was observed in all of the bacterial meningitis and mycotic meningitis patients, and in 95% of the viral meningitis patients. Among those with bacterial meningitis, the serum PCT level was more elevated in those with more serious bacterial meningitis. The PCT level in the CSF did not significantly differ among the patients with the three types of meningitis. However, the serum PCT level was very high above 0.1 microg/L in all seven bacterial meningitis patients, especially in the clinically serious cases.

[Quantitative levels of serum amyloid A protein and other proteins in cerebrospinal fluid and serum of patients with meningitis].

Serum amyloid A protein (SAA), a putative precursor of the AA protein which constitutes amyloid fibrils in secondary amyloidosis, is evaluated as a sensitive acute-phase reactant in serum. At present, SAA concentration in serum is determined by latex nephelometry, but this assay cannot detect SAA in the low concentration range lower than 10 ng/ml. We have developed a sensitive enzyme immunoassay (EIA) for determining low concentrations of SAA. The assay is reproducible, reliable and requires no pretreatment of specimen prior to assay. We measured levels of SAA by this EIA in both cerebrospinal fluid (CSF) and serum of patients with suspected meningitis, measured also levels of albumin, alpha 2 macroglobulin and C-reactive protein (CRP) to investigate if these protein levels are useful for differential diagnoses of meningitis and for indicators damage of blood-CSF barrier. The SAA reference value in CSF is 3.99 +/- 1.74 ng/ml (mean +/- SD for nonmeningitis patients). The CRP concentration in CSF in bacterial meningitis was much higher than in viral meningitis, but CRP in CSF was also high in bacterial infection other than meningitis. On the other hand, SAA concentration in CSF in these patients with any meningitis are significantly higher than the reference values of SAA (p < 0.001). However, the differences in SAA concentrations among the three types (bacterial, viral and mycotic meningitis) of meningitis were not significant.

The differential diagnosis of bacterial and aseptic meningitis using cerebrospinal fluid laboratory tests.

The lactate, lysozyme, C-reactive protein and serum amyloid-A protein concentrations in cerebrospinal fluid were measured in 11 patients with bacterial meningitis, 27 patients with aseptic meningitis and in 31 control patients. The mean concentration of each parameter was significantly higher (p less than or equal to 0.0001) in patients with bacterial meningitis than in those with aseptic meningitis or those without meningitis. The reliability of these tests in the differential diagnosis of bacterial and aseptic meningitis was compared with leucocyte counts in cerebrospinal fluid. Gram staining for bacteria, and protein and glucose levels. The cerebrospinal fluid lactate level proved to be more sensitive than lysozyme. C-reactive protein or serum amyloid-A protein and had a high degree of specificity.