Central nervous system (CNS) infections are an important public health concern worldwide. They occur commonly and are associated with high rates of mortality and morbidity. Most deaths related to CNS infections are the result of cerebral tissue injury. Neurological symptoms in survivors include physical, sensory, and cognitive disability, all of which may be permanent. Once bacteria enter the CNS, the process of replication and autolysis results in components of the bacterial wall being released into the subarachnoid space, triggering an inflammatory response characterized by the infiltration of immune cells and exudate formation. The exudate contributes to the obstruction of normal cerebrospinal fluid (CSF) flow, which may lead to hydrocephalus and raised intracranial pressure, compromised cerebral blood flow (CBF), and ischemic injury. It further coats the cerebral arteries, leading to vasospasm, vasculitis, and occlusion, with resulting ischemia and potential cerebral infarction.
Quantification of the degree of cerebral injury is inexact: disease severity is commonly evaluated by assessing the clinical status of the patient and radiological manifestations. Yet, several factors, both reversible and irreversible, may contribute to the presenting neurological status, and imaging findings manifest late in the disease course, usually once the damage is already permanent. Biomarkers for disease diagnosis, injury quantification, and monitoring are utilized frequently for other organ systems, but have yet to be applied to CNS-related cases.
Role of Biomarkers in CNS Pathology
Biomarkers are measurable objective indicators of normal function or pathology. They provide information about dynamic processes and pathogen activity that assist diagnosis, prognostication, and evaluation of treatment safety and efficacy. They can also act as surrogate markers for clinical or research end points, such as the effectiveness of novel treatments. Their quantification is user independent, and several biological fluids like blood and urine are easily obtained for investigation.
Biomarkers for CNS pathologies are gaining increasing attention and are being investigated across a spectrum of acute and chronic CNS diseases. CNS infection, trauma, hypoxia, inflammation, or degeneration results in cell damage and a collection of breakdown products in the cerebral extracellular fluid as well as increased permeability of the blood brain barrier. Diffusing along concentration gradients into the CSF and through a leaky blood-brain barrier into the bloodstream, these products become accessible measurable indicators of brain injury. The degree to which these biomarker concentrations are increased reflects the severity of injury. The cell specificity hints at the nature and, potentially, the location of injury, and sequential sampling provides information about the evolution of the damage.
Ideal biomarkers for brain injury should demonstrate high sensitivity and specificity for the brain. Their release should be associated with irreversible brain injury and reflect the temporal profile of that injury. They should appear rapidly in serum, demonstrate limited variability based on age and sex, and should be easily and speedily quantified by reliable assays. However, the task of finding such ideal biomarkers for the brain presents many challenges. The brain is a highly complex and heterogeneous organ with multiple cell types and brain diseases vary in both form and severity. CSF is a better indicator than serums in reflecting changes in the brain, but it is not always accessible. The size and amount of the biomarker infiltrating the blood stream is limited by the blood-brain barrier, so serum values may be a function of cell injury as well as the degree of blood-brain barrier disruption, which commonly occurs in brain injury. Even if CSF variability exists, biomarker concentrations may be influenced by the distance between the affected area and the CSF compartment, regional variability of biomarker proteins in the brain, and degradation by proteinases in the parenchyma or CSF. In addition, biomarker analysis is purely a quantitative measure which cannot reflect both the qualitative and quantitative functions of the brain. One way of overcoming some of these limitations is by using a panel rather than individual biomarkers as well as combining these with clinical and radiological tools.
Studies in traumatic brain injury (TBI), subarachnoid hemorrhage, dementia, Alzheimer's disease, stroke, cardiac arrest, and various other pathologies have found that biomarkers of CNS injury hold promise as diagnostic and prognostic markers.
Limitations of Biomarkers
Biomarker analysis is prone to some methodological pitfalls. The technique with which samples are collected has implications for their suitability; for example, hemolyzed blood samples may be contaminated by biomarkers released from erythrocytes. The collection tube may influence biomarker concentrations, and tubes appropriate to the biomarker of interest should be used. Samples should preferably be stored at 70°C as early as possible to prevent antigen degradation; however, this varies as a function of biomarker stability. Multiple freeze thaw cycles and prolonged storage can also lead to biomarker breakdown.
Currently, the primary method to test for biomarkers is the immunoassay, which demonstrates sensitivity, simplicity, and inexpensive administration. This technology exploits the high affinity and antibody specificity, ensuring that only the target antigen in a sample will bind, even when present in very low concentrations among other analytes. Because the interaction of antibody and antigen is not associated with a quantifiable physical or chemical change, the binding event is measured by an auxiliary reaction in which one of the immunoreactants is labeled with a substance that can easily be detected by spectrophotometry. Platforms differ on the basis of the antibody and label used to detect the antibody-antigen binding; commonly used options include enzymes (ELISAs and RIAs), fluorophores (immunofluorometric assays), and chemiluminescent compounds (chemiluminescence immunoassay).
Electrochemical immunoassays are also becoming increasingly available. Upper and lower detection limits are variable for different assays, and, therefore, comparison of reference values and pathology-related measurements across testing platforms is challenging, highlighting the need for the establishment of standardized operating and testing procedures. Large-scale multicenter trials would enable accumulation of sufficient samples for well-powered studies to establish standards, reference values, and appropriate disease-specific cutoff values. Biomarker work is still confined to dedicated laboratories or projects; however, the true translation of biomarkers from laboratory bench to bedside requires the development of rapid, user-friendly, technologically undemanding tests that can be used on demand at the hospital and clinic levels.
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