Pharmaco-proteomics opportunities for individualizing neurovascular treatment.

Neurovascular disease often involves multi-organ system injury. For example, patent foramen ovale (PFO) related ischemic strokes involve not just the brain, but also the heart, the lung, and the peripheral vascular circulation. For higher-risk but high-reward systemic therapy (e.g., thrombolytics, therapeutic hypothermia (TH), PFO closure) to be implemented safely, very careful patient selection and close monitoring of disease progression and therapeutic efficacy are imperative. For example, more than a decade after the approval of therapeutic hypothermic and intravenous thrombolysis treatments, they both remain extremely under-utilized, in part due to lack of clinical tools for patient selection or to follow therapeutic efficacy. Therefore, in understanding the complexity of the global effects of clinical neurovascular diseases and their therapies, a systemic approach may offer a unique perspective and provide tools with clinical utility. Clinical proteomic approaches may be promising to monitor systemic changes in complex multi-organ diseases - especially where the disease process can be 'sampled' in clinically accessible fluids such as blood, urine, and CSF. Here, we describe a 'pharmaco-proteomic' approach to three major challenges in translational neurovascular research directly at bedside - in order to better stratify risk, widen therapeutic windows, and explore novel targets to be validated at the bench - (i) thrombolytic treatment for ischemic stroke, (ii) therapeutic hypothermia for post-cardiac arrest syndrome, and (iii) treatment for PFO related paradoxical embolic stroke. In the future, this clinical proteomics approach may help to improve patient selection, ensure more precise clinical phenotyping for clinical trials, and individualize patient treatment.

Research and technology in neurocritical care.

The daily practice of neurointensivists focuses on the recognition of subtle changes in the neurological examination, interactions between the brain and systemic derangements, and brain physiology. Common alterations such as fever, hyperglycemia, and hypotension have different consequences in patients with brain insults compared with patients of general medical illness. Various technologies have become available or are currently being developed. The session on "research and technology" of the first neurocritical care research conference held in Houston in September of 2009 was devoted to the discussion of the current status, and the research role of state-of-the art technologies in neurocritical patients including multi-modality neuromonitoring, biomarkers, neuroimaging, and "omics" research (proteomix, genomics, and metabolomics). We have summarized the topics discussed in this session. We have provided a brief overview of the current status of these technologies, and put forward recommendations for future research applications in the field of neurocritical care.

Elevated peripheral neutrophils and matrix metalloproteinase 9 as biomarkers of functional outcome following subarachnoid hemorrhage.

There is growing evidence supporting the role of inflammation in early brain injury and cerebral vasospasm following subarachnoid hemorrhage (SAH). Matrix metalloproteinases (MMPs) are released by inflammatory cells and can mediate early brain injury via disruption of the extracellular matrix and mediate vasospasm by cleaving endothelin-1 into vasoactive fragments. We hypothesize that inflammation marked by neutrophil elevation and MMP-9 release in human SAH is associated with vasospasm and with poor clinical outcome. We enrolled consecutive SAH subjects (N = 55), banked serial blood and cerebrospinal fluid (CSF) samples, and evaluated their 3-month modified Rankin scores (mRS). Vasospasm was defined as >50% vessel caliber reduction on angiography 6-8 days post-SAH. A poor outcome was defined as mRS > 2. We compared blood leukocyte and neutrophil counts during post-SAH days 0-14 with respect to vasospasm and 3-month outcome. In a subset of SAH subjects (N = 35), we compared blood and CSF MMP-9 by enzyme-linked immunosorbent assay (ELISA) on post-SAH days 0-1, 2-3, 4-5, 6-8, and 10-14 with respect to vasospasm and to 3-month outcome. Persistent elevation of blood leukocyte (p = 0.0003) and neutrophil (p = 0.0002) counts during post-SAH days 0-14 are independently associated with vasospasm after adjustment for major confounders. In the same time period, blood neutrophil count (post-SAH days 2-3, p = 0.018), blood MMP-9 (post-SAH days 4-5, p = 0.045), and CSF MMP-9 (post-SAH days 2-3, p = 0.05) are associated with poor 3-month SAH clinical outcome. Neutrophil count correlates with blood MMP-9 (post-SAH days 6-8, R = 0.39; p = 0.055; post-SAH days 10-14, R = 0.79; p < 0.0001), and blood MMP-9 correlates with CSF MMP-9 (post-SAH days 4-5, R = 0.72; p = 0.0002). Elevation of CSF MMP-9 during post-SAH days 0-14 is associated with poor 3-month outcome (p = 0.0078). Neither CSF nor blood MMP-9 correlates with vasospasm. Early rise in blood neutrophil count and blood and CSF MMP-9 are associated with poor 3-month SAH clinical outcome. In blood, neutrophil count correlates with MMP-9 levels, suggesting that neutrophils may be an important source of blood MMP-9 early in SAH. Similarly, CSF and blood MMP-9 correlate positively early in the course of SAH, suggesting that blood may be an important source of CSF MMP-9. Blood and CSF MMP-9 are associated with clinical outcome but not with vasospasm, suggesting that MMP-9 may mediate brain injury independent of vasospasm in SAH. Future in vitro studies are needed to investigate the role of MMP-9 in SAH-related brain injury. Larger clinical studies are needed to validate blood and CSF MMP-9 as potential biomarkers for SAH outcome.

Invited article: searching for oracles? Blood biomarkers in acute stroke.

Emerging data suggest that a wide array of measurable biomarkers in blood may provide a novel window into the pathophysiology of stroke. In this review, we survey the state of progress in the field. Three specific questions are assessed. Can biomarkers augment the clinical examination and powerful brain imaging tools to enhance the accuracy of the diagnostic process? Can biomarkers be used to help triage patients for thrombolytic therapy? Can biomarkers help predict patients who are most susceptible to malignant infarction? Many encouraging molecular candidates have been found that appear to match the known cascades of neurovascular injury after stroke. However, whether these putative biomarkers may indeed have direct clinical utility remains to be quantitatively validated. Larger clinical trials are warranted to establish the sensitivity and specificity of biomarkers for routine use in clinical stroke.

Adult acute disseminated encephalomyelitis associated with poststreptococcal infection.

Acute disseminated encephalomyelitis (ADEM) is a monophasic illness that is thought to develop from antigenic mimicry with antibodies having cross-reactivity to host epitopes in the nervous system. The disorder typically follows an exanthematous or recent viral infection. In contrast, complications from bacterial poststreptococcal infections more commonly give rise to disorders in the pediatric population including Sydenham's chorea, pediatric autoimmune neuropsychiatric disorders, and ADEM. We present the novel case of documented streptococcal pharyngitis and elevated antideoxyribonuclease B (ADNB) titers in an adult giving rise to ADEM. Furthermore, the absence of basal ganglia abnormalities on MRI and the degree of leukocytosis in the CSF distinguish the adult form of ADEM from childhood ADEM and adult viral demyelinating diseases.

Repeated pulses of serotonin required for long-term facilitation activate mitogen-activated protein kinase in sensory neurons of Aplysia.

Long-term facilitation of the connections between the sensory and motor neurons of the gill-withdrawal reflex in Aplysia requires five repeated pulses of serotonin (5-HT). The repeated pulses of 5-HT initiate a cascade of gene activation that leads ultimately to the growth of new synaptic connections. Several genes in this process have been identified, including the transcriptional regulators apCREB-1, apCREB-2, apC/EBP, and the cell adhesion molecule apCAM, which is thought to be involved in the formation of new synaptic connections. Here we report that the transcriptional regulators apCREB-2 and apC/EBP, as well as a peptide derived from the cytoplasmic domain of apCAM, are phosphorylated in vitro by Aplysia mitogen-activated protein kinase (apMAPK). We have cloned the cDNA encoding apMAPK and show that apMAPK activity is increased in sensory neurons treated with repeated pulses of 5-HT and by the cAMP pathway. These results suggest that apMAPK may participate with cAMP-dependent protein kinase during long-term facilitation in sensory cells by modifying some of the key elements involved in the consolidation of short- to long-lasting changes in synaptic strength.