Frank P. Zemlan

C-tau biomarker of neuronal damage in severe brain injured patients: association with elevated intracranial pressure and clinical outcome

Following traumatic brain injury, the neuronally-localized intracellular protein MAP-tau is proteolytically cleaved (C-tau) and gains access to cerebrospinal fluid (CSF) and serum. The present study compared initial CSF C-tau levels, initial Glasgow Coma Scale (GCS) scores and elevated intracranial pressure (ICP) as predictors of clinical outcome. In this preliminary, prospective study of consecutive severe traumatic brain injured patients (TBI) clinical outcome was quantified with the Glasgow Outcome Scale (GOS) at discharge (n=28). Sensitivity and specificity of initial C-tau levels and initial GCS scores as predictors of clinical outcome is reported. To assess disease specificity C-tau levels were compared between TBI patients and neurologic (n=87) and non-neurologic control patients (n=67). Initial CSF C-tau levels were elevated 40,000 fold in TBI patients compared to either neurologic or non-neurologic control patients (P<0.001). Initial C-tau levels were correlated with clinical outcome (P=0.006) and were a significant predictor of dichotomized clinical outcome (P=0.011) demonstrating a sensitivity of prediction of 92% and a specificity of 94%. Initial C-tau levels were also a significant predictor of subsequent ICP with higher initial C-tau levels associated with elevated ICP (P=0.014). Initial GCS score were correlated with clinical outcome (P=0.026) and demonstrated a sensitivity of 50% and a specificity of 100% for predicting dichotomized clinical outcome. Statistical analysis indicated that initial C-tau levels and initial GCS scores were independent predictors of clinical outcome. The present preliminary study demonstrates that initial CSF C-tau levels are a significant predictor of ICP and clinical outcome with particular sensitivity for identifying severe TBI patients with good clinical outcome. Future studies employing a larger sample size and clinical outcome assessment at longer periods after hospitalization will be needed to determine the utility of initial C-tau levels as a clinical biomarker in TBI.

Superoxide dismutase activity in Alzheimer's disease: possible mechanism for paired helical filament formation ☆

Activity of the free radical scavenging enzyme, superoxide dismutase (SOD-1), was determined in fibroblast cell lines derived from familial Alzheimers patients, trisomy 21 patients and normal controls. In the present study, SOD-1 activity was significantly elevated by 30% in Alzheimers cell lines when compared to normal euploid cell lines. As SOD-1 activity is known to be elevated about 50% in trisomy 21 patients, these cell lines were included as a control for tissue culture and assay conditions. In the present study, SOD-1 activity was significantly increased by 42 +/- 11% in trisomy 21 patients. The elevation in SOD-1 activity observed in the familial Alzheimers patients supports the theory that paired helical filaments are synthesized in Alzheimers disease by free radical hydroxylation of proline residues in paired helical filament precursor protein(s).

Ascending and descending projections from nucleus reticularis magnocellularis and nucleus reticularis gigantocellularis: an autoradiographic and horseradish peroxidase study in the rat

The projections of the rostral medulla were studied using retrograde and orthograde transport techniques in the rat. The present horseradish peroxidase (HRP) studies indicate that the ventral portion of nucleus reticularis gigantocellularis (NGC) and nucleus reticularis magnocellularis (NMC) project to both rostral and caudal levels of the spinal cord, while dorsal NGC projects only to the rostral cord. A differential density distribution of labeled cells was observed, with the greatest density of NGC-spinal neurons located rostral to the level of the inferior olive; and the greatest density of NMC-spinal neurons located caudally. This differential density distribution, when coupled with microiontophoretic application of [3H]amino acids allowed relatively independent labeling of the adjacent NGC- and NMC-spinal systems. On the basis of the HRP and autoradiographic studies 3 separate regions were delineated: dorsal NGC, ventral NGC and NMC. Descending projections from NGC were observed to the lateral vestibular nucleus, facial nucleus, hypoglossal nucleus and nucleus cuneatus. At cervical levels NGC fibers projected through the ventral and ventrolateral columns. Terminal fields were observed in laminae VII, VIII and to a lesser extent in IX. Labeled NGC fibers became difficult to follow by thoracic levels, which is consistent with the present HRP results. A continuum of descending NGC projections was observed with dorsally located NGC neurons projecting bilaterally through the ventral columns, and ventrally located NGC cells projecting through the ipsilateral ventrolateral columns. Ascending projections from NGC to the motor nucleus of V, trochlear nucleus, oculomotor nucleus, Edinger-Westphal nucleus, the ventral aspect of the periaqueductal gray, the deep and intermediate layers of the superior colliculus, nucleus parafasicularis and centromedianus, the Fields of Forel and the dorsal and lateral hypothalamic nuclei were observed. Descending projections from NMC to the dorsal nucleus of the vagus, hypoglossal nucleus, nucleus commissuralis and intercalatus were observed. At cervical levels, fibers project through the ipsilateral lateral columns, particularly its dorsal aspect. Terminal fields are located ipsilaterally in laminae IV, V and VI, and bilaterally in VII, VIII and X. NMC projections continue through caudal levels of the spinal cord including a projection to the ipsilateral intermediolateral columns. Ascending NMC projections are limited to the ventral pontine reticular formation.(ABSTRACT TRUNCATED AT 400 WORDS)

Serum S-100B and cleaved-tau are poor predictors of long-term outcome after mild traumatic brain injury

Primary objective: To determine the relationship of serum S-100B and C-tau levels to long-term outcome after mild traumatic brain injury (mild TBI). Research design: A prospective study of 35 mild TBI subjects presenting to the emergency department. Methods and procedures: Six hour serum S-100B and C-tau levels compared to 3-month Rivermead Post Concussion Questionnaire (RPCQ) scores and post-concussive syndrome (PCS). Main outcomes and results: The linear correlation between marker levels and RPCQ scores was weak (S-100B: r = 0.071, C-tau: r = −0.21). There was no statistically significant correlation between marker levels and 3-month PCS (S-100B: AUC = 0.589, 95%CI. 038, 0.80; C-tau: AUC = 0.634, 95%CI 0.43, 0.84). The sensitivity of these markers ranged from 43.8–56.3% and the specificity from 35.7–71.4%. Conclusions: Initial serum S-100B and C-tau levels appear to be poor predictors of 3-month outcome after mild TBI.

The arachidonic acid 5‐lipoxygenase inhibitor nordihydroguaiaretic acid inhibits tumor necrosis factor α activation of microglia and extends survival of G93A‐SOD1 transgenic mice

Familial forms of amyotrophic lateral sclerosis (ALS) can be caused by mutations in copper, zinc‐superoxide dismutase (SOD1). Mice expressing SOD1 mutants demonstrate a robust neuroinflammatory reaction characterized, in part, by up‐regulation of tumor necrosis factor alpha (TNFα) and its primary receptor TNF‐RI. In an effort to identify small molecule inhibitors of neuroinflammation useful in treatment of ALS, a microglial culture system was established to identify TNFα antagonists. Walker EOC‐20 microglia cells were stimulated with recombinant TNFα, with or without inhibitors, and the cell response was indexed by NO2– output. Three hundred and fifty‐five rationally selected compounds were included in this bioassay. The arachidonic acid 5‐lipoxygenase (5LOX) and tyrosine kinase inhibitor nordihydroguaiaretic acid (NDGA), a natural dicatechol, was one of the most potent non‐cytotoxic antagonists tested (IC50 8 ± 3 μm). Investigation of the G93A‐SOD1 mouse model for ALS revealed increased message and protein levels of 5LOX at 120 days of age. Oral NDGA (2500 p.p.m.) significantly extended lifespan and slowed motor dysfunction in this mouse, when administration was begun relatively late in life (90 days). NDGA extended median total lifespan of G93A‐SOD1 mice by 10%, and life expectancy following start of treatment was extended by 32%. Disease‐associated gliosis and cleaved microtubule‐associated tau protein, an indicator of axon damage, were likewise reduced by NDGA. Thus, TNFα antagonists and especially 5LOX inhibitors might offer new opportunities for treatment of ALS.

Nucleus cuneiformis and pain modulation: anatomy and behavioral pharmacology

The anatomical substrate and behavioral pharmacology of stimulation-produced analgesia resulting from electrical stimulation of the pontomesencephalic nucleus cuneiformis (NCF) was determined in the present study. Maximum increase in nociceptive tail-flick latencies following NCF stimulation occurred during the first 5 min post stimulation and decreased afterwards. The increased reflex latency could be attenuated by prior treatment with the narcotic antagonist, naloxone or the cholinergic antagonist, scopolamine. The anatomical projections of NCF were identified in autoradiographic and histochemical studies. Ipsilateral fibers coursed caudal from the NCF injection site through the ventral pontine reticular formation to innervate nucleus raphe magnus and the ipsilateral nucleus magnocellularis. At rostral medullary levels fibers coursed dorsolateral to innervate the ipsilateral nucleus reticularis parvocellularis. Descending contralateral fibers crossed through the decussation of the superior cerebellar peduncle, then coursed ventrolaterally projecting to the contralateral nucleus magnocellularis. Two primary groups of ascending fibers were observed. The dorsally located group ascended through the central tegmental tract projecting to the dorsal raphe, ipsilateral periaqueductal gray, nucleus parafascicularis and centromedianus, the intermediolateral and lateral thalamic nuclei. The ventral group coursed ventrolateral from the injection site projecting to the substantia nigra, zona compacta, ventral tegmental area of Tsai, zona incerta, Fields of Forel, lateral hypothalamic nucleus and nucleus reuniens. These anatomic and behavioral data suggest that NCF plays an important role in sensory/motor integration relevant to pain transmission.

Chapter 26 Serotonin receptor subtypes and the modulation of pain transmission

Publisher Summary This chapter describes the serotonin receptor subtypes and discusses the modulation of pain transmission. Three major subtypes of the serotonin 5-hydroxytryptamine (5HT) receptor have been identified: 5HT 1 , 5HT 2 , and 5HT 3 . The subtypes have different anatomical distributions that are important for understanding the unique effect each receptor subtype has on primary afferent and central pain transmission. The chapter reviews data on all three major 5HT receptor subtypes focusing on 5HT 1 receptors. 5HT resulted in muscle contractions by a direct action on 5HT receptors located on smooth muscle, an action preferentially antagonized by phenoxybenzamine (dibenzyline) and therefore referred to as the D-receptor. 5HT produces muscle contraction by an indirect effect on cholinergic ganglionic neurons innervating the guinea pig ileum; an effect of 5HT preferentially antagonized by morphine (M-receptors). Intradermal administration of 5HT mimics the effects of mechanical or chemical insult in man, including vasodilation (flare response), edema formation, and the perception of pain.

Serum cleaved tau does not predict postconcussion syndrome after mild traumatic brain injury.

OBJECTIVES Our objective was to determine if the biomarker for axonal injury, serum cleaved tau (C-tau), predicts postconcussion syndrome (PCS) in adults after mild traumatic brain injury (mTBI). METHODS C-tau was measured from blood obtained in the emergency department. Outcome was assessed at 3 months post injury using the Rivermead Postconcussion Symptoms Questionnaire and Acute Medical Outcomes SF-36v2 Health Survey (SF-36). RESULTS Of 50 patients, there were 15 patients with detectable levels of C-tau, 10 patients with abnormal findings on initial head computed tomography (CT) and 22 patients with PCS. One-third of patients with detectable C-tau and 14.3% of patients without detectable C-tau had abnormal findings on head CT (P = .143). Serum C-tau was not detected more frequently in patients with PCS than those without, neither for all patients (P = .115) nor the subgroup with negative head CT (P = .253). CONCLUSIONS C-tau is a poor predictor of PCS after mTBI regardless of head CT result.

Hypothermia as an adjunctive treatment for severe bacterial meningitis

Brain injury due to bacterial meningitis results in a high mortality rate and significant neurologic sequelae in survivors. The objective of this study was to determine if the application of moderate hypothermia shortly after the administration of antibiotics would attenuate the inflammatory response and increase in intracranial pressure that occurs in meningitis. For this study we used a rabbit model of severe Group B streptococcal meningitis. The first component of this study evaluated the effects of hypothermia on blood-brain barrier function and markers of inflammation in meningitic animals. The second part of the study evaluated the effects of hypothermia on intracranial pressure, cerebral perfusion pressure and brain edema. This study demonstrates that the use of hypothermia preserves CSF/serum glucose ratio, decreases CSF protein and nitric oxide and attenuates myeloperoxidase activity in brain tissue. In the second part of this study we show a decrease in intracranial pressure, an improvement in cerebral perfusion pressure and a decrease in cerebral edema in hypothermic meningitic animals. We conclude that in the treatment of severe bacterial meningitis, the application of moderate hypothermia initiated shortly after antibiotic therapy improves short-term physiologic measures associated with brain injury.

5-HT1A receptors mediate the effect of the bulbospinal serotonin system on spinal dorsal horn nociceptive neurons.

The present study examined whether the effect of stimulation of the nucleus raphe magnus (NRM) is mediated by spinal cord dorsal horn serotonin1A (5-HT1A) receptors in the rat. This hypothesis predicts that nociceptive dorsal horn units inhibited by NRM stimulation or iontophoretic 5-HT application would also be inhibited by iontophoresis of the selective 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone. A total of 78 dorsal horn wide-dynamic-range neurons were recorded. Overall, 62% of the cells tested (48/78) were responsive to electrical stimulation of the NRM with the predominant response being inhibitory (38/48; 79%). Fifty-eight cells were tested for their response to both NRM stimulation and 8-OH-DPAT iontophoresis: 20/58 cells were inhibited by NRM stimulation and 50% of the cells inhibited by NRM stimulation were also inhibited by 8-OH-DPAT. Fifty-two cells were tested for their response to both NRM stimulation and buspirone iontophoresis: 14/52 cells were inhibited by NRM stimulation with 9/14 similarly inhibited by buspirone. To examine whether exogenously applied serotonin produced an effect through 5-HT1A receptors, the effect of both 5-HT and 8-OH-DPAT iontophoresis was tested on 57 dorsal horn neurons. The majority of cells (25/57) were inhibited by 5-HT application; 15/25 were similarly inhibited by 8-OH-DPAT. The response of 48 dorsal horn cells to 5-HT and buspirone iontophoresis was compared. Forty-four percent (21/48) of the cells were inhibited by 5-HT; 16/21 were also inhibited by buspirone.(ABSTRACT TRUNCATED AT 250 WORDS)