ERCC1 is a prognostic biomarker in locally advanced head and neck cancer: results from a randomised, phase II trial.

BACKGROUND: Cisplatin-radiotherapy is a preferred standard for locally advanced, head and neck squamous cell carcinoma (HNSCC). However, the cisplatin-attributable survival benefit is small and toxicity substantial. A biomarker of cisplatin resistance could guide treatment selection and spare morbidity. The ERCC1-XPF nuclease is critical to DNA repair pathways resolving cisplatin-induced lesions. METHODS: In a phase II trial, patients with untreated Stage III-IVb HNSCC were randomised to cisplatin-radiotherapy with/without erlotinib. Archived primary tumours were available from 90 of 204 patients for this planned substudy. Semi-quantitative ERCC1 protein expression (H-score) was determined using the FL297, 4F9, and 8F1 antibodies. The primary analysis evaluated the relationship between continuous ERCC1 protein expression and progression-free survival (PFS). Secondary analyses included two pre-specified ERCC1 cutpoints and performance in HPV-associated disease. RESULTS: Higher ERCC1 expression was associated with inferior PFS, as measured by the specific antibodies FL297 (HR=2.5, 95% CI=1.1-5.9, P=0.03) and 4F9 (HR=3.0, 95% CI=1.2-7.8, P=0.02). Patients with increased vs decreased/normal ERCC1 expression experienced inferior PFS (HR=4.8 for FL297, P=0.003; HR=5.5 for 4F9, P=0.007). This threshold remained prognostic in HPV-associated disease. CONCLUSION: ERCC1-XPF protein expression by the specific FL297 and 4F9 antibodies is prognostic in patients undergoing definitive cisplatin-radiotherapy for HNSCC, irrespective of HPV status.

5-HTTLPR genotype and gender, but not chronic fluoxetine administration, are associated with cortical TREK1 protein expression in rhesus macaques.

TREK1 is a widely expressed background potassium channel. Similar to mice treated with selective serotonin reuptake inhibitors (SSRIs), TREK1 knockout mice are resistant to depression-like behavior and have elevated serotonin levels leading to speculation that TREK1 inhibition may contribute to the therapeutic effects of SSRIs. This study examined how chronic fluoxetine administration and a common functional polymorphism in the serotonin-transporter-linked promoter region (5-HTTLPR) influence cortical TREK1 expression in 24 rhesus monkeys. The short rh5-HTTLPR allele as well as female gender were associated with reduced cortical TREK1 protein expression but chronic SSRI administration had no effect. These results suggest that serotonin may influence TREK1, but that chronic SSRI treatment does not result in long lasting changes in cortical TREK1 protein expression. TREK1 gender differences may be related to gender differences in serotonin and require further research.

A functional alternative splicing mutation in human tryptophan hydroxylase-2.

The brain serotonergic system has an essential role in the physiological functions of the central nervous system and dysregulation of serotonin (5-HT) homeostasis has been implicated in many neuropsychiatric disorders. The tryptophan hydroxylase-2 (TPH2) gene is the rate-limiting enzyme in brain 5-HT synthesis, and thus is an ideal candidate gene for understanding the role of dysregulation of brain serotonergic homeostasis. Here, we characterized a common, but functional single-nucleotide polymorphism (SNP rs1386493) in the TPH2 gene, which decreases efficiency of normal RNA splicing, resulting in a truncated TPH2 protein (TPH2-TR) by alternative splicing. TPH2-TR, which lacks TPH2 enzyme activity, dominant-negatively affects full-length TPH2 function, causing reduced 5-HT production. The predicted mRNA for TPH2-TR is present in postmortem brain of rs1386493 carriers. The rs13864923 variant does not appear to be overrepresented in either global or multiplex depression cohorts. However, in combination with other gene variants linked to 5-HT homeostasis, this variant may exhibit important epistatic influences.

Chronic corticosterone administration down-regulates metabotropic glutamate receptor 5 protein expression in the rat hippocampus.

Several lines of evidence suggest a dysfunctional glutamate system in major depressive disorder (MDD). Recently, we reported reduced levels of metabotropic glutamate receptor subtype 5 (mGluR5) in postmortem brains in MDD, however the neurobiological mechanisms that induce these abnormalities are unclear. In the present study, we examined the effect of chronic corticosterone (CORT) administration on the expression of mGluR5 protein and mRNA in the rat frontal cortex and hippocampus. Rats were injected with CORT (40 mg/kg s.c.) or vehicled once daily for 21 days. The expression of mGluR5 protein and mRNA was assessed by Western blotting and quantitative real-time PCR (qPCR). In addition, mGluR1 protein was measured in the same animals. The results revealed that while there was a significant reduction (-27%, P=0.0006) in mGluR5 protein expression in the hippocampus from CORT treated rats, mRNA levels were unchanged. Also unchanged were mGluR5 mRNA and protein levels in the frontal cortex and mGluR1 protein levels in both brain regions. Our findings provide the first evidence that chronic CORT exposure regulates the expression of mGluR5 and are in line with previous postmortem and imaging studies showing reduced mGluR5 in MDD. Our findings suggest that elevated levels of glucocorticoids may contribute to impairments in glutamate neurotransmission in MDD.

Differential regulation of the serotonin 1 A transcriptional modulators five prime repressor element under dual repression-1 and nuclear-deformed epidermal autoregulatory factor by chronic stress.

Chronic stress is known to affect brain areas involved in learning and emotional responses. These changes, thought to be related to the development of cognitive deficits are evident in major depressive disorder and other stress-related pathophysiologies. The serotonin-related transcription factors (Freud-1/CC2D1A; five prime repressor element under dual repression/coiled-coil C2 domain 1a, and NUDR/Deaf-1; nuclear-deformed epidermal autoregulatory factor) are two important regulators of the 5-HT1A receptor. Using Western blotting and quantitative real-time polymerase chain reaction (qPCR) we examined the expression of mRNA and proteins for Freud-1, NUDR, and the 5-HT1A receptor in the prefrontal cortex (PFC) of male rats exposed to chronic restraint stress (CRS; 6 h/day for 21 days). After 21 days of CRS, significant reductions in both Freud-1 mRNA and protein were observed in the PFC (36.8% and 32%, respectively; P<0.001), while the levels of both NUDR protein and mRNA did not change significantly. Consistent with reduced Freud-1 protein, 5-HT1A receptor mRNA levels were equally upregulated in the PFC, while protein levels actually declined, suggesting post-transcriptional receptor downregulation. The data suggest that CRS produces distinct alterations in the serotonin system specifically altering Freud-1 and the 5-HT1A receptor in the PFC of the male rat while having no effect on NUDR. These results point to the importance of understanding the mechanism for the differential regulation of Freud-1 and NUDR in the PFC as a basis for understanding the related effects of chronic stress on the serotonin system (serotonin-related transcription factors) and stress-related disorders like depression.

3,4-Methylenedioxymethamphetamine induces differential regulation of tryptophan hydroxylase 2 protein and mRNA levels in the rat dorsal raphe nucleus.

Previous investigations with 3,4-methylenedioxymethamphetamine (MDMA) have suggested that administration of this drug results in a degeneration of 5-HT nerve terminals and subsequent alterations in 5-HT neurotransmission. However, only limited investigations have examined the effects of MDMA on the dorsal raphe nucleus. The present study was designed to assess the effect of MDMA on the rate-limiting enzyme in 5-HT biosynthesis, tryptophan hydroxylase (TPH), by measuring TPH2 protein and mRNA levels in rat dorsal raphe (DR) nucleus. Rats were administered MDMA (20 mg/kg, s.c.) or saline twice daily for 4 days and killed 14 days later. Tissue sections of the DR were processed for quantitative immunoautoradiography and in situ hybridization histochemistry for measurements of the levels of TPH2-immunoreactivity (IR) and TPH2 mRNA. To assess 5-HT axon terminal integrity after MDMA treatment, the density of 5-HT transporter (SERT) binding sites was measured by quantitative autoradiography using [125I]RTI-55 ((-)-2beta-carbomethoxy-3 beta-(4-iodophenyl) tropane) ((125)I-RTI-55) as a ligand. TPH2-IR levels were significantly decreased by 45% in the mid DR and by 40% in the caudal DR in the MDMA-treated rats compared with saline-injected rats. In contrast, TPH2 mRNA levels were significantly increased by 24% in the mid DR and by 12% in the caudal DR. MDMA treatment significantly decreased (125)I-RTI-55 labeled SERT binding sites in the striatum, nucleus accumbens and cingulate cortex demonstrating a loss of 5-HT terminals. The increase in TPH2 mRNA levels in both the mid DR and caudal DR of MDMA-treated rats may reflect a compensatory mechanism in the injured 5-HT neurons to increase TPH2 protein synthesis. Taken together, our results suggest that a serious defect occurs in the biosynthesis of TPH2 in the DR following MDMA administration.

Increased corticotropin-releasing hormone immunoreactivity in monoamine-containing pontine nuclei of depressed suicide men.

A number of clinical investigations and postmortem brain studies have provided evidence that excessive corticotropin-releasing hormone (CRH) secretion and neurotransmission is involved in the pathophysiology of depressive illness, and several studies have suggested that the hyperactivity in CRH neurotransmission extends beyond the hypothalamus involving several extra-hypothalamic brain regions. The present study was designed to test the hypothesis that CRH levels are increased in specific brainstem regions of suicide victims with a diagnosis of major depression. Frozen tissue sections of the pons containing the locus coeruleus and caudal raphe nuclei from 11 matched pairs of depressed suicide and control male subjects were processed for radioimmunocytochemistry using a primary antiserum to CRH and a ([125])I-IgG secondary antibody. The optical density corresponding to the level of CRH-immunoreactivity (IR) was quantified in specific pontine regions from the film autoradiographic images. The level of CRH-IR was increased by 30% in the locus coeruleus, 39% in the median raphe and 45% in the caudal dorsal raphe in the depressed suicide subjects compared to controls. No difference in CRH-IR was found in the dorsal tegmentum or medial parabrachial nucleus between the subject groups. These findings reveal that CRH-IR levels are specifically increased in norepinephrine- and serotonin-containing pontine nuclei of depressed suicide men, and thus they are consistent with the hypothesis that CRH neurotransmission is elevated in extra-hypothalamic brain regions of depressed subjects.

Localized decrease in serotonin transporter-immunoreactive axons in the prefrontal cortex of depressed subjects committing suicide.

A variety of postmortem brain studies and clinical investigations have provided evidence that reduced serotonin neurotransmission is associated with suicidal behavior and depression, and several serotonergic parameters have been found to be altered in the prefrontal cortex of suicide victims. However, the integrity of the serotonin innervation of the prefrontal cortex in mood disorders has not been directly investigated. The present study used immunocytochemical methods and an antibody against the serotonin transporter to examine the relative density of serotonin axons in the dorsolateral prefrontal cortex of suicide victims with a diagnosis of major depression. The mean total length of serotonin transporter-immunoreactive axons per unit area was unchanged in layers 2 and 4 of area 46 in the depressed suicide subjects compared to controls, but was significantly (P < 0.01) decreased by 24% in layer 6 in the depressed suicide group. The total length of serotonin transporter-positive axons in layer 6 was reduced in eight of the 12 depressed suicide subjects compared to their matched control subjects. These findings reveal that depressed subjects who have committed suicide exhibit a lamina-specific reduction in a marker of serotonin axons in the dorsolateral prefrontal cortex that may reflect an alteration in cortical serotonin neurotransmission.

Increased transcription of the tyrosine hydroxylase gene in individual locus coeruleus neurons following footshock stress.

Footshock-evoked change in transcriptional activity of tyrosine hydroxylase in neurons of the locus coeruleus was examined using an intron-specific in situ hybridization histochemical technique. A significant increase in the cellular concentration of tyrosine hydroxylase primary transcripts was found in locus coeruleus neurons 3h following 30 min of intermittent footshock. However, the footshock-induced increase in tyrosine hydroxylase transcription was not homogeneously expressed in locus coeruleus neurons. Similarly, administration of the alpha(2)-adrenergic receptor antagonist idazoxan produced a significant increase in the cellular concentration of tyrosine hydroxylase primary transcripts that was heterogeneously distributed among locus coeruleus neurons. Both footshock and idazoxan significantly increased the regional levels of tyrosine hydroxylase messenger RNA in the locus coeruleus. The time-course of changes in tyrosine hydroxylase transcription rate and messenger RNA levels in the locus coeruleus was examined after a 15 min exposure to footshock. A robust increase in tyrosine hydroxylase transcription rate was found at the end of 15 min of footshock, which remained elevated for 6h and was back to the control levels by 24h. In contrast, in response to a 15 min period of footshock tyrosine hydroxylase messenger RNA concentrations in the locus coeruleus did not increase until 6h and remained elevated at 24h. These findings demonstrate that transcription of the tyrosine hydroxylase gene in locus coeruleus neurons in response to footshock stress occurs rapidly, is sustained for many hours and is heterogeneously distributed. These data also suggest that the increase in tyrosine hydroxylase messenger RNA following footshock is mediated, at least in part, by an increase in tyrosine hydroxylase gene transcription.

Normal cellular levels of synaptophysin mRNA expression in the prefrontal cortex of subjects with schizophrenia.

BACKGROUND: Previous studies have reported that the 38-kd synaptic vesicle-associated protein, synaptophysin, is decreased in the prefrontal cortex of subjects with schizophrenia. METHODS: To determine whether the decreased protein levels reflect diminished expression of the synaptophysin gene by prefrontal cortex neurons, we used in situ hybridization histochemistry to determine the cellular levels of synaptophysin messenger RNA in prefrontal cortex area 9 from 10 matched pairs of schizophrenic and normal control subjects. RESULTS: Neither the density of neurons with detectable levels of synaptophysin messenger RNA nor the mean level of synaptophysin messenger RNA expression per neuron differed between schizophrenic and control subjects in any cortical layer. CONCLUSIONS: These findings indicate that the expression of synaptophysin messenger RNA is not altered in this brain region in schizophrenia. Consequently, reduced levels of synaptophysin protein in the prefrontal cortex of subjects with schizophrenia are more likely to reflect either posttranscriptional abnormalities of synaptophysin in prefrontal cortex neurons or a diminished number of axonal projections to the prefrontal cortex from other brain regions.

Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia.

BACKGROUND: Markers of gamma-aminobutyric acid (GABA) neurotransmission seem to be altered in the prefrontal cortex (PFC) of subjects with schizophrenia. We sought to determine whether the expression of the messenger RNA (mRNA) for the synthesizing enzyme of GABA, glutamic acid decarboxylase67 (GAD67), is decreased in the PFC of subjects with schizophrenia, whether this change is present in all or only some GABA neurons, and whether long-term treatment with haloperidol decanoate contributes to altered GAD67 mRNA expression. METHODS: Tissue sections from 10 pairs of subjects with schizophrenia and control subjects and 4 pairs of haloperidol-treated and control monkeys were processed for in situ hybridization histochemical analysis with sulfur-35-labeled oligonucleotide probes for GAD67 mRNA and exposed to nuclear emulsion. Within each layer of PFC area 9, neurons expressing a detectable level of GAD67 mRNA were quantified for cell density and the relative level of mRNA expression per cell (grain density per neuron). RESULTS: In subjects with schizophrenia, the density of labeled neurons was significantly (P<.05) decreased by 25% to 35% in cortical layers 3 to 5. In contrast, the mean grain density per labeled neuron did not differ across subject groups. Similar analyses in monkeys revealed no effect of long-term haloperidol treatment on either the density of the labeled neurons or the grain density per labeled neuron. CONCLUSIONS: These findings indicate that in subjects with schizophrenia, GAD67 mRNA expression is relatively unaltered in most PFC GABA neurons but is reduced below a detectable level in a subset of GABA neurons. Altered GABA neurotransmission in this subset may contribute to PFC dysfunction in subjects with schizophrenia.

Analysis of tyrosine hydroxylase gene transcription using an intron specific probe.

The nuclear run-on assay is the most commonly used technique to determine transcription rates of specific genes such as tyrosine hydroxylase. Its application to studies in the nervous system is problematic, however, as a result of limitations in sensitivity and the loss of anatomical integrity. We observed that the relative levels of tyrosine hydroxylase intron 2-containing RNA using a ribonuclease protection assay in the adrenal medulla changed in response to pharmacological treatments consistently with changes shown by the nuclear run-on assay. Our results indicate that measures of tyrosine hydroxylase primary transcript levels offer an alternative to the nuclear run-on assay and validate the application of intron-specific in situ hybridization as a means of assessing the relative transcriptional activity of the tyrosine hydroxylase gene. Similar quantitative results were obtained using intron-specific in situ hybridization with oligonucleotide probes specific for rat tyrosine hydroxylase intron 2. Furthermore, we observed that intron-specific in situ hybridization could be used to measure tyrosine hydroxylase transcription rates in the locus coeruleus, providing resolution at the level of single neurons. Thus, measuring the levels of tyrosine hydroxylase intron 2 provides a sensitive measure of tyrosine hydroxylase transcription rate that can be applied to the study of brain catecholaminergic neurons.

Regional distribution and cellular expression of tryptophan hydroxylase messenger RNA in postmortem human brainstem and pineal gland.

The characterization and cellular localization of tryptophan hydroxylase mRNA in the human brainstem and pineal gland were investigated by using northern blot analysis and in situ hybridization histochemistry. Northern analysis of human pineal gland revealed the presence of two mRNA species that were absent in RNA isolated from human raphe. In situ hybridization experiments revealed very dense hybridization signal corresponding to tryptophan hydroxylase mRNA in cells throughout the pineal gland. In contrast, tryptophan hydroxylase mRNA was heterogeneously distributed in neurons in the dorsal and median raphe nuclei. Within the dorsal raphe, the ventrolateral and interfascicular subnuclei contained the greatest number of tryptophan hydroxylase mRNA-positive neurons. Also, the cellular concentration of tryptophan hydroxylase mRNA varied widely within the dorsal and median raphe. Comparison of the cellular concentration of tryptophan hydroxylase mRNA between the pineal gland and the raphe nuclei revealed an 11- and 46-fold greater average grain density of tryptophan hydroxylase mRNA positive cells in the pineal gland compared with the dorsal and median raphe, respectively. These findings are the first to demonstrate the cellular localization of tryptophan hydroxylase mRNA in the human brain and pineal gland as well as heterogeneity in the cellular concentration within and between these tissues.

A standardized protocol for the initial evaluation and documentation of mild brain injury.

OBJECTIVE: To present a protocol for the initial assessment and documentation of mild brain injury, a protocol that is used within the Department of Physical Education at the United States Military Academy. BACKGROUND: Recently, much attention has been given to the assessment and management of mild brain injury by the sports medicine community. Although the classification of and management strategies for mild brain injury have been well disputed, most experts agree on the essentials of the sideline or initial evaluation. According to leading experts, if an athlete has experienced an episode of mild brain injury, the initial signs and symptoms, as well as the course of those signs and symptoms, should be documented. DESCRIPTION: Although many athletic training texts formerly discussed techniques for evaluating an episode of mild brain injury, few present an objective protocol to follow. Our protocol includes 3 components. The first component is the initial evaluation, which incorporates serial observations during the first 20 minutes after injury, with neurologic checks every 5 minutes. The second component includes a take-home sheet for athletes not referred to a physician for further evaluation. The third part of the protocol is a 24-hour postinjury follow-up examination for any signs or symptoms of postconcussion syndrome. Finally, we present the indications for referral to a physician for further evaluation. CLINICAL ADVANTAGES/RECOMMENDATIONS: Using a standard protocol to guide evaluation and to document the initial course of signs and symptoms after mild brain injury allows the sports medicine staff to make better management decisions. In addition, patient instructions and the course of follow-up evaluations can be improved if a standard protocol is employed. Our protocol has been developed to meet the needs both of athletes who are exposed to mild brain injury on a daily basis and of the certified athletic trainers who initially evaluate them; the protocol can be adapted to the individual needs of each athletic training setting.

Oscillatory effects of repeated morphine on shock-induced hypoalgesia and beta-endorphin.

Recent research indicates that the sensitization that results from repeated drug or non-drug stress exposure may develop into a pattern of alternating increases and decreases (i.e., oscillation) in response to each subsequent stressor exposure. Oscillation, with or without prior sensitization, has been observed for a number of drug and non-drug stressors, and for various neurochemical and endocrine endpoints. The present studies investigated whether oscillation also occurs in the behavioral and endocrine effects of repeated morphine treatment and if a drug that normalizes the mood swings of bipolar disorder in humans will also attenuate drug oscillation in this animal model. In the first experiment, rats were given 1-5 pretreatments with morphine (15 mg/kg, i.p.), separated by 1-week intervals with the last injection occurring 1 hour prior to being tested for stressor-induced (i.e., 5 seconds, 2-mA electric footshock) hypoalgesia, as measured by latency to paw-lift or jump from a hot-plate. Plasma beta-endorphin also was measured. The second experiment replicated the behavioral findings of the first study and, in addition, assessed the effect of continuous lithium chloride, in the drinking water, on morphine-induced oscillation. Caffeine was used as a partial control for the lithium. The results were that one injection of morphine enhanced stress-induced hypoalgesia and subsequent morphine administrations resulted in oscillation. Beta-endorphin exhibited sensitization but not oscillation, suggesting that it did not mediate oscillation of the behavioral response. In addition, lithium, but not caffeine, eliminated oscillations of the behavioral response without affecting its initial enhancement.

The effects of lithium on a potential cycling model of bipolar disorder.

1. Although bipolar disorder constitutes a major public health problem, with a high risk of suicide and an economic cost exceeding that of unipolar depression, it has received comparatively little attention, particularly at the basic science level. Perhaps as a result of this neglect, there is currently no animal model able to simulate the cyclicity which is its defining characteristic. 2. Consequently, drug development in this area is meager and has proceeded serendipitously rather than empirically. 3. The authors have recently reported that repeated exposure to cocaine and other stressors can induce an oscillation or cycling in a host of neurochemical and physiological systems. 4. In order to test whether such cycling might be of potential relevance to bipolar disorder, the authors examined whether cocaine-induced cyclicity of amphetamine-evoked efflux of dopamine from slices of rat nucleus accumbens and striatum and/or cocaine induced oscillation of a behavior, stress-induced hypoalgesia, could be prevented by lithium, the agent of choice in treating this disease. 5. The authors report that prophylactic treatment with lithium, completely and specifically prevented oscillations in each instance. This may represent an important initial step toward the development of the first cycling model of bipolar disorder.

Oscillatory-sensitization model of repeated drug exposure: cocaine's effects on shock-induced hypoalgesia.

1. The authors have recently proposed that the sensitization produced by repeated exposure to drugs or stress may give way to an alternating pattern of increases and decreases in the response to each subsequent exposure (i.e., oscillate), as the limits of the physiological system are approached. 2. Evidence for oscillation has been obtained for 6 drug/non-drug stressors and 9 neurochemical or endocrine endpoints. This paper extends the model to a behavioral outcome. 3. In the first experiment, rats were given 0, 1, 2 or 3 pretreatments with cocaine hydrochloride (COC; 12 mg/kg i.p.), separated by 1-week intervals, and then were tested for footshock-induced hypoalgesia (5-sec, 2-mA), as measured by withdrawal latencies from a hot-plate. 4. The second experiment replicated the first and extended the pretreatment sequence to 5 COC injections. 5. In both experiments, shock significantly increased latencies over the no-shock controls. COC enhanced shock-induced hypoalgesia and this sensitization reached its maximum after 2 COC pretreatments. Thereafter, oscillation developed such that the sensitization was attenuated by 3 as compared to 2 COC injections, enhanced by 4 injections, and reattenuated after 5 COC pretreatments. 6. These data complement other findings by demonstrating that the oscillation model extends to a stress-induced behavioral outcome.

Differential distribution of corticotropin-releasing hormone immunoreactive axons in monoaminergic nuclei of the human brainstem.

Corticotropin-releasing hormone (CRH) has been implicated in a variety of physiological and behavioral responses to stress, as well as in the pathophysiology of certain psychiatric disorders. Although studies in rodents support a neuromodulatory influence of CRH on monoamine neurotransmission in a number of brain regions, little information in available to support a similar role for CRH in the human brain. The present study used immunocytochemistry to characterize the anatomical organization of CRH-immunoreactive axons in the human brainstem. Substantial regional differences in the density and distribution of CRH-immunoreactive axons were found in the dopamine-, noradrenaline- and serotonin-containing cell body regions of the human brainstem. Dense networks of CRH-immunoreactive axons were found in the medial subnuclei of the ventral mesencephalon and in the dorsolateral region of the locus coeruleus. Moderate densities of CRH-positive fibers were located in the median and dorsal raphe, whereas lower numbers of CRH-labeled axons appeared in the substantia nigra pars compacta. In addition, differences in CRH innervation density were observed within each region. For example, the dorsal tier of the substantia nigra contained a greater density of CRH-labeled axons than the ventral tier. In all monoamine-containing nuclei, CRH-labeled axons exhibited numerous beaded varicosities and fine intervaricose segments. The differential distribution of CRH-containing axons across these human brainstem nuclei suggests that the influence of CRH on monoamine function may be neurotransmitter-specific.

Sensitivity and specificity of 99mTc-HMPAO SPECT cerebral perfusion measurements during the first 48 hours for the localization of cerebral infarction.

BACKGROUND AND PURPOSE: There is no routinely used method for imaging the location of the extent and severity of cerebral tissue perfusion changes during the first hours of ischemic stroke, the period during which therapeutic intervention is most likely to be successful. Cerebral perfusion measurements with single-photon emission CT (SPECT) may potentially provide this information rapidly and noninvasively. In this study, the sensitivity and specificity of 99mTc-hexamethylpropyleneamine oxime (HMPAO) SPECT cerebral perfusion measurements during the first 48 hours of cerebral ischemia for the localization of cerebral infarction were determined. METHODS: One hundred and four patients with acute ischemic stroke underwent 99mTc-HMPAO SPECT and CT scanning during the first 48 hours. In each patient, the location of the SPECT perfusion abnormality was compared with the location of infarction on a second brain CT acquired at a mean of 8 days after stroke. RESULTS: During the first 48 hours of ischemic stroke, the sensitivity of 99mTc-HMPAO SPECT in locating the site of infarction was 79% (110/139), and the specificity was 95% (362/381). SPECT was more sensitive in the localization of the vascular territory of cortical infarction (sensitivity, 93%) than pure subcortical infarcts (sensitivity, 47%). During the first 48 hours, SPECT was significantly more sensitive than brain CT (sensitivity of brain CT during the first 48 hours, 35%; P < .001, Mann-Whitney U test). CONCLUSIONS: HMPAO SPECT measurement provides a widely available and practical technique of locating cerebral ischemia acutely and demonstrates high sensitivity and specificity within the first 48 hours for the localization of the vascular territory of cerebral infarction. It is most sensitive for cortical ischemia but is limited by its resolution in the subcortex, particularly of white matter perfusion changes.