A selective dopamine reuptake inhibitor improves prefrontal cortex-dependent cognitive function: potential relevance to attention deficit hyperactivity disorder.

Drugs used to treat attention deficit hyperactivity disorder (ADHD) improve prefrontal cortex (PFC)-dependent cognitive function. The majority of ADHD-related treatments act either as dual norepinephrine (NE) and dopamine (DA) reuptake inhibitors (psychostimulants) or selective NE reuptake inhibitors (SNRIs). Certain benztropine analogs act as highly selective DA reuptake inhibitors while lacking the reinforcing actions, and thus abuse potential, of psychostimulants. To assess the potential use of these compounds in the treatment of ADHD, we examined the effects of a well-characterized benztropine analog, AHN 2-005, on performance of rats in a PFC-dependent delayed-alternation task of spatial working memory. Similar to that seen with all drugs currently approved for ADHD, AHN 2-005 dose-dependently improved performance in this task. Clinically-relevant doses of psychostimulants and SNRIs elevate NE and DA preferentially in the PFC. Despite the selectivity of this compound for the DA transporter, additional microdialysis studies demonstrated that a cognition-enhancing dose of AHN 2-005 that lacked locomotor activating effects increased extracellular levels of both DA and NE in the PFC. AHN 2-005 produced a larger increase in extracellular DA in the nucleus accumbens, although the magnitude of this was well below that seen with motor activating doses of psychostimulants. Collectively, these observations suggest that benztropine analogs may be efficacious in the treatment of ADHD or other disorders associated with PFC dysfunction. These studies provide a strong rationale for future research focused on the neural mechanisms contributing to the cognition-enhancing actions and the potential clinical utility of AHN 2-005 and related compounds. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Early intervention with a small molecule inhibitor for tumor necrosis factor-α prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease.

BACKGROUND: Chronic neuroinflammation is an important component of Alzheimer's disease and could contribute to neuronal dysfunction, injury and loss that lead to disease progression. Multiple clinical studies implicate tumor necrosis factor-α as an inflammatory mediator of neurodegeneration in patients with Alzheimer's because of elevated levels of this cytokine in the cerebrospinal fluid, hippocampus and cortex. Current Alzheimer's disease interventions are symptomatic treatments with limited efficacy that do not address etiology. Thus, a critical need exists for novel treatments directed towards modifying the pathophysiology and progression. METHODS: To investigate the effect of early immune modulation on neuroinflammation and cognitive outcome, we treated triple transgenic Alzheimer's disease mice (harboring PS1(M146V), APP(Swe), and tau(P301L) transgenes) with the small molecule tumor necrosis factor-α inhibitors, 3,6'-dithiothalidomide and thalidomide, beginning at four months of age. At this young age, mice do not exhibit plaque or tau pathology but do show mild intraneuronal amyloid beta protein staining and a robust increase in tumor necrosis factor-α. After 10 weeks of treatment, cognitive performance was assessed using radial arm maze and neuroinflammation was assessed using biochemical, stereological and flow cytometric endpoints. RESULTS: 3,6'-dithiothalidomide reduced tumor necrosis factor-α mRNA and protein levels in the brain and improved working memory performance and the ratio of resting to reactive microglia in the hippocampus of triple transgenic mice. In comparison to non-transgenic controls, triple transgenic Alzheimer's disease mice had increased total numbers of infiltrating peripheral monomyelocytic/granulocytic leukocytes with enhanced intracytoplasmic tumor necrosis factor-α, which was reduced after treatment with 3,6'-dithiothalidomide. CONCLUSIONS: These results suggest that modulation of tumor necrosis factor-α with small molecule inhibitors is safe and effective with potential for the long-term prevention and treatment of Alzheimer's disease.

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.

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 efficacy and safety of the melatonin agonist beta-methyl-6-chloromelatonin in primary insomnia: a randomized, placebo-controlled, crossover clinical trial.

BACKGROUND: While melatonin agonists are known to regulate circadian sleep rhythms, it is not clear whether melatonin agonists have a direct soporific effect. It has been suggested that melatonin's soporific effect is secondary to its ability to induce hypothermia. beta-Methyl-6-chloromelatonin is a high-affinity melatonin receptor agonist that is not associated with hypothermia. The purpose of the present study was to determine if the melatonin agonist beta-methyl-6-chloromelatonin has a direct soporific effect in subjects with primary insomnia. METHOD: A double-blind, placebo-controlled, crossover safety and efficacy study of 20 mg, 50 mg, and 100 mg of beta-methyl-6-chloromelatonin and placebo was conducted in subjects with DSM-IV-TR primary insomnia. Of 84 subjects screened, 40 progressed to randomly receive each of 3 beta-methyl-6-chloromelatonin doses or placebo on each of 2 consecutive nights with 5-day washout periods between treatments. The effect of treatment on both polysomnographic and subjectively measured sleep parameters, next-morning psychomotor performance, and safety measures was determined. The primary outcome measure was latency to persistent sleep measured by polysomnography. RESULTS: A significant effect of beta-methyl-6-chloromelatonin on the primary efficacy variable, latency to persistent sleep, was observed (p = .0003). The 20-mg dose resulted in a significant 31% improvement in sleep latency compared with placebo, while significant 32% and 41% improvements were observed at the 50-mg and 100-mg doses, respectively (20 mg, p = .0082; 50 mg, p = .0062; 100 mg, p < .0001). Similarly, a significant effect of beta-methyl-6-chloromelatonin on subjective measures of time to fall asleep occurred (p = .0050), with significant improvement observed at both the 50-mg and 100-mg doses (p = .0350 and .0198, respectively) and a trend toward improvement observed at the 20-mg dose (p = .0582). Adverse events were mild to moderate in severity and did not differ in frequency between beta-methyl-6-chloromelatonin and placebo treatments. CONCLUSION: beta-Methyl-6-chloromelatonin significantly decreases both objective and subjective measures of sleep latency in subjects with primary insomnia. Thus, these data suggest that mel-atonin agonists may exert a direct soporific effect, as previous research indicates that beta-methyl-6-chloromelatonin is not associated with changes in body temperature, heart rate, or blood pressure.

Cleaved-tau: a biomarker of neuronal damage after traumatic brain injury.

Previous studies from our laboratory indicate that traumatic brain injury (TBI) in humans results in proteolysis of neuronally-localized, intracellular microtubule associated protein (MAP)-tau to produce cleaved tau (C-tau). The present study evaluated the utility of C-tau to function as a biomarker of neuronal injury and as a biomarker for evaluating neuroprotectant drug efficacy in a controlled cortical impact model of rat TBI. Brain C-tau was determined in rats subjected to controlled cortical impact-induced mild, moderate or severe levels of TBI. A significant severity-dependent increase in C-tau levels was observed in the cortex and hippocampus (1.5-8-fold) of TBI rats compared to shams 72 h after impact. C-tau rat brain and serum time course was determined by measuring levels at 0.25, 6, 24, 48, 72 and 168 h after TBI. A significant time-dependent increase in C-tau levels was observed in ipsilateral cortex (5-16-fold) and hippocampus (2-40-fold) compared to sham animals. C-tau levels increased as early as 6 h after TBI with peak C-tau levels observed 168 h after injury. Elevated brain C-tau levels were associated with TBI-induced tissue loss, which was histologically determined. The effect of cyclosporin-A (CsA), previously demonstrated to be neuroprotective in rat TBI, on brain C-tau levels was examined. CsA (20 mg/kg i.p., 15 min and 24 h after TBI) significantly attenuated the TBI-induced increase in hippocampal C-tau levels observed in vehicle-treated animals confirming CsA's neuroprotectant effect. CsA treatment also lowered ipsilateral cortical C-tau levels, although it did not reach statistical significance. CsA's neuroprotectant effect was confirmed utilizing histologic measures of TBI-induced tissue loss. In addition, serum C-tau levels were significantly increased 6 h after TBI but not at later time points. These results suggest that C-tau is a reliable, quantitative biomarker for evaluating TBI-induced neuronal injury and a potential biomarker of neuroprotectant drug efficacy in the rat TBI model. Serum data suggests that C-tau levels are dependent both on a compromised blood-brain barrier as well as release of TBI biomarkers from the brain, which has implications for the study of human serum TBI biomarkers.

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.

Serum cleaved tau protein levels and clinical outcome in adult patients with closed head injury.

STUDY OBJECTIVE: Intracranial injuries (ICI) are associated with high mortality and morbidity. Unfortunately, tools for diagnosis and risk stratification of ICIs are limited in the emergency department setting. We determine the relationship between the presence or absence of a detectable cleaved serum tau protein (tau(c)), ICI, and outcome at hospital discharge in adults with closed head injuries (CHI). METHODS: This was a prospective pilot study of adult patients with CHI presenting to the ED of an urban Level I trauma center. Patients presenting within 10 hours of a CHI who underwent a head computed tomographic (CT) scan were eligible. A blood sample was collected at presentation and the tau(c) level was measured. Initial Glasgow Coma Scale scores and demographic information were recorded. A chart review was performed to determine outcome and final readings on the initial head CT scan. RESULTS: Patients were dichotomized to 1 of 2 groups, those with an ICI (n=17) and those with an isolated skull fracture or no CT abnormality (NICI) (n=11). The 2 groups were similar in regard to demographic composition, mechanism of injury, and coexisting injuries. A tau(c) level of more than 0 was associated with an increased chance of an ICI on the initial head CT scan (odds ratio 11.25; 95% confidence interval [CI] 1.17 to 108.4) and a greater chance of poor outcome, defined as death while in hospital or transfer to a nursing home at hospital discharge (odds ratio 8.17; 95% CI 1.42 to 47). CONCLUSION: A tau(c) level of more than 0 is associated with a greater chance of intracranial injury and poor outcome in patients with CHI.

Analgesia after lesions of nucleus reticularis magnocellularis: differential effect on supraspinal versus spinal pain reflexes.

The present studies examine the effect of bilateral electrolytic lesions of descending fibers arising from nucleus reticularis magnocellularis (NMC) on responding to noxious peripheral thermal or mechanical stimulation and on spinal cord monoamine levels. The lesion effects were quantified by examining two supraspinally organized pain responses, the hot plate latency and vocalization threshold and two spinally organized nociceptive reflexes, tail flick latency and hind limb flexion threshold. Following interruption of descending NMC fibers, a profound analgesia was observed on supraspinally organized pain responses. Assay of spinal cord serotonin (5-HT) indicated that the NMC lesions also destroyed appreciable numbers of descending 5-HT fibers of passage originating in nucleus raphe magnus (RM). A modest hypersensitivity to pain occurred after control lesions in RM suggesting that the analgesia observed after NMC lesions would have been even more pronounced if RM fibers of passage had not been concomitantly destroyed. To assess whether the analgesia observed after NMC lesions was due to non-specific destruction of a given volume of reticular tissue, control lesions were placed in nucleus subcoeruleus (NSC). NSC lesions resulted in a hypersensitivity to pain and significant depletion of spinal cord noradrenaline (NA). These data suggest both that the analgesia observed after NMC lesions was not due to non-specific destruction of the reticular formation, and that descending NSC NA fibers tonically suppress pain. The above analgesic effects were observed exclusively on supraspinally organized pain responses, not spinally organized nociceptive reflexes. This supported previous studies demonstrating differential descending control of nociception in the spinal versus intact preparations. In summary, the present data suggest that descending NMC fibers tonically suppress ascending pain transmission.