Neurochemical studies of Alzheimer''s disease

Age differences in the representation of semantic information may underlie the cognitive decline observed in aging. The objective of the present study was to determine to what extent elderly and young subjects agreed in the representations of semantic categories. Ninety elderly (77 women, 13 men) and 90 young (74 women, 16 men) participants wrote down the first four associations evoked by each of 30 semantic category names. Results showed differences between the two groups in items selected as most common responses (MCRs); frequency of occurrence of the MCRs differed between the two groups in 21 semantic categories. Results suggest that young and elderly subjects hold different representations of semantic categories and also highlight the importance of using age-appropriate norms in the evaluation of cognitive functions in aging.     

Postmortem studies in schizophrenia

The past decade has seen renewed interest in the neuropathology of schizophrenia. The advent of new postmortem techniques and functional imaging, along with a greater understanding of the neuropsychology of schizophrenia, have provided many new clues to the nature of the underlying brain dysfunction in this disorder. There has also been a greater understanding of the presence of severe cognitive dysfunction among many elderly persons with schizophrenia. In this article, a series of investigations are described that seek to answer basic questions about the neuropathology of schizophrenia, in particular as it pertains to cognitive impairment. The first study describes neuropathological findings in 100 consecutively autopsied persons with schizophrenia, the majority of whom had had detailed antemortem assessments. Results from this first study prompted the conclusion that schizophrenia is not characterized by classical, histologically identifiable neuropathology. Moreover, most cases of dementia in schizophrenia are probably not the result of neuropathologically identifiable dementing illnesses. The next four studies examined chemical markers that are altered in Alzheimer's disease and some other dementing conditions and have also been suggested to be abnormal in schizophrenia: choline acetyltransferase, catecholamines and indolamines, neuropeptides, and synaptic proteins. Schizophrenia cases as a group did not show a cholinergic deficit; nor did they differ from elderly comparison cases with respect to cortical catecholamines and indolamines. Among the schizophrenia cases, however, cognitive impairment was negatively correlated with choline acetyltransferase activity. Those with cognitive impairment showed evidence of cortical noradrenergic and serotonergic deficits. Neuropeptide deficits were also present in schizophrenia, but their pattern differed from that seen in Alzheimer's disease. Increased synaptic protein activity was found in the cingulate cortex of persons with schizophrenia, and this activity was correlated with schizophrenia symptoms. From this second series of studies, it was concluded that some biological measures in schizophrenia may be related to cognitive impairment (e.g., cortical amines), whereas others may be related to diagnosis (e.g., neuropeptide deficits). In addition, synaptic organization may correlate with schizophrenia symptoms.     

Endocrine syndromes in schizophrenia in the light of pathologoanatomic studies

A study of the endocrine profile (all glands of endocrine secretion) in 33 cases of schizophrenia, where the autopsy was performed not later than 6 hours after death, permitted the author to distinguish 4 syndromes: normal functional activity (24%), hypofunction (30%), the stress-syndrome (33%) and dysfunction (12%). It is stressed that their formation is effected by several factors: the age of the patient, duration of illness, medication, cause of death, etc. The found changes in the glands are less severe in comparison to the previously described changes seen in senile dementia. These changes are considered in the aspect of pathomorphosis of schizophrenia.     

Experimental studies on figural after-effects in Japan.

"Many experimental studies on figural aftereffects in Japan were reviewed under several topics. Gibson's 'curved line'; Kohler and Wallach's 'size' effect; 'displacement' effect and 'field strength'; temporal factors; some other spatial factors; luminance; contrast, illuminance, and color; and some related experiments. Concerning some typical experimental situations, the effects of spatial and temporal variables were analyzed quantitatively, and some mathematical functions to relate these variables to the amount of after-effects were examined." Several additional factors and experiments are discussed. 64 references. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurochemical studies of human narcolepsy: alpha-adrenergic receptor autoradiography of human narcoleptic brain and brainstem

Studies of human and canine narcolepsy-cataplexy syndrome suggest that noradrenergic function may be abnormal. We used quantitative autoradiography to assess noradrenergic alpha-1 and alpha-2 receptors in several regions of seven human narcoleptic and 18 control brains using [3H]prazosin to evaluate alpha-1 receptors, and [3H]UK14304 and [3H]rauwolscine to evaluate alpha-2 receptors. Specific blocking agents were used in combination with the tritiated ligands to assess alpha-1 and alpha-2 receptor subtypes. Although we found few statistically significant differences between narcoleptic and control brains, there were a number of trends. [3H]Prazosin binding to sites in the amygdala, globus pallidus and putamen was reduced by 22-68%, whereas binding was increased by 40% to the inferior olive and by 84% to portions of the dorsal pons. Binding was similar to control values in other regions. In all seven brainstem regions that were evaluated, the ratio of alpha-1b receptor binding to alpha-1a receptor binding was increased. Binding of [3H]UK14304 was increased by 35-74% in the caudate nucleus, putamen and portions of the amygdala and pons. [3H]rauwolscine binding data suggested that increase of alpha-2 receptor binding in the dorsal pons were not due to effects at the imidazole receptor. findings suggest that noradrenergic function may be altered in specific regions of the brain and brainstem in human narcolepsy, although the absence of statistical significance indicates that these trends should be considered preliminary. The trend toward a relative increase of alpha-1b receptor binding in narcoleptic brainstem is consistent with data from studies of canine narcolepsy and suggests that altered activity at this receptor may contribute to the pathogenesis of human narcolepsy. Studies of additional brains will be required to confirm these findings.     

A review of longitudinal studies of cognitive functions in schizophrenia patients

We examined whether differences in health were associated with different probabilities of marital transitions in a longitudinal study, using Cox proportional hazard analysis. Data on approximately 10,000 Dutch persons of the GLOBE study, aged 15-74 years, were used for this purpose. The study started in 1991 and study subjects have been followed for 4.5 years. Of the four marital transitions studied (marriage among never married and divorced persons, and divorce and bereavement among married persons), only divorce among married persons was associated with health status: married persons who reported four or more subjective health complaints or two or more chronic conditions were, respectively, 1.5 and two times more likely to become divorced during follow-up than persons without these health problems. Since hardly any other studies have examined the role of health selection in marital transition with longitudinal data, more research is required before firm conclusions can be drawn. It can be concluded, however, that the frequently made assumption that health selection contributes only little to the explanation of health differences between marital status groups, seems, at least for the divorced, not justified.     

Attention deficits in childhood-onset schizophrenia: Reaction time studies.

The hypothesis of continuity between childhood-onset and adult schizophrenia was tested by comparing the performance of 15 patients with childhood-onset schizophrenia and 52 age-matched controls on 2 reaction time paradigms that have been used to study adult schizophrenia. On simple reaction time to tones with regular and irregular preparatory intervals of 2, 4, and 8 s, patients showed greater effects of the length of the preparatory interval in the regular condition and greater effects of the preparatory interval (girls only) and the preceding preparatory interval in the irregular series. On simple reaction time to random lights and tones, patients were faster on sequences than cross-modal sequences compared with controls. Overall, patients were much slower than controls in both paradigms. The results suggest similar attention dysfunction as is found in adult schizophrenia and thus are consistent with the continuity hypothesis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A critical review of genetic studies of schizophrenia. I. Epidemiological and brain studies

Many patients with chronic posttraumatic stress disorder (PTSD) suffer from comorbid major depression. The present study examines the responsiveness of such dual-diagnosis patients to antidepressant medication. Subjects were enrolled in the PTSD medication clinic at the San Diego Veterans Affairs Medical Center. Inclusion criteria were current diagnoses of PTSD and major depression, at least 6 months of regular participation in the clinic, and treatment with antidepressant medication at therapeutic levels and durations. Exclusion criteria were current drug or alcohol abuse, primary psychotic illness, and poor compliance or frequent missed appointments. Among 72 patients meeting inclusion and exclusion criteria, 50% were estimated to be substantially improved, on the basis of Clinical Global Evaluation (CGE) scores of 2 or 1, after remaining on the same antidepressant treatment regimen at therapeutic doses for at least 1 month. Antidepressant medications affecting predominantly serotonin reuptake (sertraline, fluoxetine) were associated with better outcomes than antidepressants affecting predominantly norepinephrine reuptake (nortriptyline, desipramine).     

Neurochemical asymmetry of human cerebral hemispheres

The study was concerned with cholinesterase activity and acetylcholine content in the cortical tissue of the human brain, obtained in autopsy and during neurosurgery. A symmetry of cholinesterase activity was found in paired cortical zones of the cutaneous analyser, while in the cortical substance of the motor analyser, its activity was asymmetrical. In the parietal cortex the acetylcholine content was almost equal on two sides; a tendency to its asymmetry was noted in the frontal area. These characteristics of interhemispheric transmitter-enzyme relations between symmetrical cortical centres seem to be a link in the mechanism underlying paired and asymmetrical activity of cortical areas of the cerebral hemispheres in humans.     

Mental processes in schizophrenia (based on data from neuropsychological studies)

Features were studied of brain organization of mental processes in schizophrenic patients during the period of aggravation of the condition, using methods common in neuropsychological diagnosis. Faulty mental functions are analyzed in connection with clinical manifestations. Groups have been identified of patients having particular neuropsychological and clinical characteristics.     

Neurochemical classification of myenteric neurons in the guinea-pig ileum

A strategy has been developed to identify and quantify the different neurochemical populations of myenteric neurons in the guinea-pig ileum using double-labelling fluorescence immunohistochemistry of whole-mount preparations. First, six histochemical markers were used to identify exclusive, non-overlapping populations of nerve cell bodies. They included immunoreactivity for the calcium binding proteins calbindin and calretinin, the neuropeptides vasoactive intestinal polypeptide, substance P and somatostatin, and the amine, 5-hydroxytryptamine. The sizes of these populations of neurons were established directly or indirectly in double-labelling experiments using a marker for all nerve cell bodies. Each of these exclusive populations was further subdivided into classes by other markers, including immunoreactivity for enkephalins and neurofilament protein triplet. The size of each class was then established directly or by calculation. These distinct, neurochemically-identified classes were related to other published work on the histochemistry, electrophysiology and retrograde labelling of enteric neurons and to the simple Dogiel morphological classification. A classification scheme, consistent with previous studies, is proposed. It includes 14 distinct classes of myenteric neurons and accounts for nearly all neurons in the myenteric plexus of the guinea-pig ileum.     

Current status of conducting function tests in repeated dose toxicity studies in Japan

It seems desirable to conduct as many function tests as possible in repeated dose toxicity studies, but is it practicable? The current status of conducting function tests in repeated dose toxicity studies in Japan was investigated by a literature survey of more than one thousand papers published in seven Japanese toxicology journals during the past 10 years and by a questionnaire survey directed to toxicologists among the Japan Pharmaceutical Manufacturers Association (JPMA) member companies. The function tests often carried out in repeated dose toxicity studies were, for example: 1) electro-retinography (ERG) and visually evoked potential (VEP) for visual test and tonometer for intraocular pressure; 2) auricular reflex, evoked response audiometry (ERA) and auditory brainstem response (ABR) to sound stimuli; 3) respiration and heart rate, electrocardiogram (ECG) and blood pressure by noninvasive cuff methods or using electronic devices such as telemetry; 4) body temperature, spontaneous motility and some adaptation tests (using rotarod and sloped plate in rats); 5) indocyanin (ICG) or bromosulfophtalein (BSP) for hepatic test; 6) phenolsulfonphtalein (PSP) and creatinine clearance for renal test; and 7) immunoglobulin, leukocyte phagocytosis, lymphocyte blastgenesis and natural killer cell (NK) for immuno-reaction test. Limitations to conducting function tests in repeated dose toxicity studies and issues to be resolved were discussed, based on questions and suggestions given by the respondents to the questionnaire. Although it certainly seemed desirable to conduct as many function tests as possible in repeated dose toxicity studies, most of the function tests so far introduced into toxicity studies were not satisfactory, because those tests could not be carried out under the restricted conditions of repeated dose toxicity studies, and not much reliable data from function tests were obtainable. A variety of function tests should firstly be incorporated into single dose toxicity studies together with development of a new concept for methodology in safety pharmacology.     

Integrative and sealing-over recoveries from schizophrenia: distinguishing case studies

Fast-2, a membrane mutant of Paramecium aurelia, is due to a single-gene mutation and has behavioral abnormalities. Intracellular recordings through changes of external solutions were made. The mutant membrane hyperpolarized when it encountered solutions with low K+ concentration. This hyperpolarization and other associated activities were best observed in Ca- or Na-solutions devoid of K+. Membrane potential was plotted against the concentration of K+ (0.5 to 16 mM) in solutions of fixed Na+ or Ca++ concentration. The slopes of the curves for the mutant membrane were steeper than those for the wild type at the lower concentrations of K+. Inclusion of 2 mM tetraethylammonium chloride (TEA-Cl) counteracted the mutational effects. Spontaneous action potentials in Ba-solution and the electrically evoked action potentials in various solutions are normal in this mutant. We conclude that the resting permeability to K+ relative to the permeabilities to Na+ and Ca++ has been increased by the mutation.     

Neurochemical effects of static magnetic field exposure

BACKGROUND: Ketorolac is a parenteral nonsteroidal antiinflammatory drug (NSAID). Two features have limited its clinical utility: tendency to elicit kidney failure and inability to produce complete analgesia. Because most NSAIDs are weak acids (pKa 3-5) and become concentrated in acidic tissues, such as injured and inflamed tissues, we hypothesized that local administration may enhance its analgesic efficacy while lowering the potential for systemic complications. METHODS: We conducted a randomized, placebo-controlled study of 60 group I-II (American Society of Anesthesiology criteria) mastectomy patients, 20 in each group. Near the end of surgery and every 6 h postoperatively, 20 ml of the study solution containing normal saline with or without 30 mg of ketorolac were administered simultaneously either via a Jackson-Pratt drain or intravenously in a double-blind fashion. The quality of pain control, the amount and character of the drain fluid, incidence of nausea and vomiting, length of stay in the postoperative care unit, and amount of morphine used for treatment of break-through pain were recorded. RESULTS: Intraoperative administration of ketorolac resulted in better quality of pain control in the immediate postoperative period regardless of route of administration. The incidence of nausea was significantly higher in the placebo group, and drain output in the ketorolac groups did not exceed the output in the placebo group. CONCLUSION: Analgesic of the locally administered ketorolac is equally effective to the efficacy of ketorolac administered intravenously.     

Neurochemical changes and current pharmacological approaches in craniocerebral trauma

In recent years, our knowledge concerning pathophysiological changes in brain metabolism after traumatic brain injury (TBI) has greatly expanded. This, in turn, has enabled the development of specific pharmacological strategies for the supplementary treatment of brain-injured patients with the aim of reducing secondary brain damage. The present article focuses on the pathophysiology of TBI and the possibilities for pharmacological intervention. While some of the substances reviewed and presently used in the treatment of TBI, others are under experimental and clinical evaluation at different stages.     

Neurochemical coding for feeding in sheep and steers.

Feeding responses of 8 sheep (wethers) and 8 steers were compared following intraventricular injection of a-adrenergic agonists and antagonists in 2-hr tests. In sheep, injection of the a-agonist levonorepinephrine (l-NE) (140-1,120 nmoles) increased feed intakes 288% and 388% compared with intakes following synthetic cerebrospinal fluid. This response was blocked by the a-antagonist phenoxybenzamine, whereas the antagonist alone decreased feed intake. The a-adrenergic antagonist propranolol did not modify the l-NE response. A purer but weaker a-agonist levophenylephrine, also resulted in increased feed intake that was blocked by phenoxybenzamine. In contrast to the feeding responses of sheep, l-NE caused hypophagia in steers, reducing intakes as much as 58% in 2-hr tests over doses ranging 42-27,800 nmoles. Phenoxybenzamine blocked the l-NE-induced hypophagia in steers; when injected alone, it increased feed intakes 181% of control values. Changes in feeding following l-NE injections are probably not attributable to changes in temperature, fat mobilization, or stupor. Data support the hypothesis of an a-adrenergic-coded system for feeding in sheep and for satiety in steers. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neurochemical monitoring of fatal middle cerebral artery infarction

BACKGROUND: Microdialysis is a method for neurochemical monitoring that has been applied more frequently over the past few years in patients suffering from subarachnoid hemorrhage, acute brain injury, and stroke. It is used to study the course of extracellular molecules of low molecular weight, such as excitatory amino acids or metabolic end products. CASE DESCRIPTION: We report the case of a 43-year-old patient suffering from left hemispheric stroke with a space-occupying postischemic edema leading to a considerable mass effect on the contralateral side. For treatment of severe edema, hypothermia was initiated. The microdialysis and intracranial pressure probe were placed into the noninfarcted hemisphere. A massive increase in levels of glutamate, glycerine, and the lactate-pyruvate ratio was measured 24 hours before intracranial pressure elevation was observed and brain death occurred. CONCLUSIONS: Monitoring excitatory amino acids, glycerine as a membrane component, and lactate-pyruvate ratio as an energy marker by microdialysis is a useful tool to increase our understanding of biochemical events in secondary brain damage. For future prevention of secondary ischemia in patients with massive stroke, close neurochemical monitoring might be valuable to improve therapy, particularly in the critically ill.     

Neurochemical studies of narcosis: a comparison between the effects of nitrous oxide and hyperbaric nitrogen on the dopaminergic nigro-striatal pathway

Inert gas narcosis is a neurological syndrome inducing several psychomotor disorders. Nitrogen narcosis represents the major cause of performances decrease concerning divers, in the depth range of 30 to 90 meters (0.3 to 0.9 MegaPascal). As narcosis affects motor functions, we chose to study the nigro-striatal dopaminergic pathway owing to its involvement in psychomotor disorders. The aim of this study is to compare, in the Sprague-Dawley rats striatium, changes in extracellular concentrations of Dopamine and its metabolites: Dihydroxyphenylacetic Acid (DOPAC) and Homovanillic Acid (HVA) under a normobaric narcosis (20; 40, and 60% of Nitrous Oxide (N2O)) on one hand, and under 0.9 MegaPascal of Nitrox (Nitrogen Oxygen normoxic mixture) on the other hand. In fact, if these two conditions are similar, normobaric narcosis would allow us to explain nitrogen narcosis mechanisms without any pressure effect. The first emergence of Dopamine and metabolites variations occurs around 40% of N2O. Dopamine decreases by 45% and is accompanied by a DOPAC diminution of 7% while HVA concentrations remain constant. Under 60% N2O, these decrease have a greater amplitude. The Dopamine variations obtained under 0.9 Mpa of Nitrox are closed to alterations induced by 60% of N2O (DA decreases by 70%).