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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To search for potential mechanism that might alter synaptic transmission following Abeta increase we have examined the presynaptic component of transmitter release. As parameters of synaptic transmission that might underlie presynaptic mechanisms, we have used paired-pulse facilitation (PPF), post-tetanic potentiation (PTP), and synaptic fatigue (SF) at the connection between the hippocampal Schaffer-collateral pathway and CA1 pyramidal neurons in approximately 5 month old double transgenic mice overexpressing the mutated form of amyloid precursor protein (APPK670N, M671L) and presenilin 1 (PS1M146V). While the presynaptic mechanisms of PPF and PTP were not compromised in the APP/PS1 mice, SF was more pronounced in the double transgenic animals. The percentage of the 40th fEPSP slope over the first during the tetanus was 18 -/+ 3% in APP/PS1 vs. 26 -/+ 2% in WT. Thus, it is likely that presynaptic mechanisms underlying SF but not PPF and PTP, may account for synaptic dysfunction in APP/PS1 mice.
Curr Alzheimer Res 2005 Apr
PMID:Synaptic fatigue is more pronounced in the APP/PS1 transgenic mouse model of Alzheimer's disease. 1597 10

ASTA Medica is developing retigabine, a carbamic acid ethyl ester and a selective potassium channel opener, for the treatment of complex partial seizures. Phase II trials have commenced [249117], and a multicenter placebo-controlled dosage-finding study has begun in Europe and Australia [392702]. Retigabine is also undergoing phase II testing in Germany, Switzerland, Russia and the US for the potential treatment of epilepsy [323383]. Phase II trials have shown >50% reduction in seizure frequency in 12 of 35 patients with refractory epilepsy [373379]. Phase I clinical trials for epilepsy were successfully completed in Germany in 1995 [180371]. Single and multiple dose trials demonstrated the tolerability and favorable pharmacokinetic behavior of the compound [264306]. The compound showed good compatibility and exhibits an antisense anticonvulsive effect in various preclinical epilepsy models [250565,299344]. Side effects of mild to moderate tiredness, fatigue and nausea were observed [276123]. The spectrum of activity of retigabine resembles that of valproate, but its potency is greater and toxicity is reduced [373379]. The mechanism of action of retigabine is probably multifactorial. Research has shown that retigabine acts as a selective K+ channel opener in neuronal cells and this can be expected to contribute to its anticonvulsant effect [273670]. In addition it demonstrates potentiation of GABA transmission and possibly also weak modulation of sodium and calcium channels [299344]. Retigabine also has neuroprotective activity with potential for the treatment of stroke and neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease and multiple sclerosis [249381]. In February 2000, Lehman Brothers predicted product launch could be as early as 2002 for epilepsy in the US [357788]. In February 1999, Lehman Brothers predicted that the first major launch date of the drug would be 2003, and the year of peak sales to be 2011 [319225].
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PMID:Retigabine (ASTA Medica). 1603 7

We review here aggression-related human psychopathologies and propose that human aggressiveness is mainly due to three major factors: (i) brain dysfunction affecting aggression-controlling brain centers (e.g. in certain types of brain lesions, epilepsy, Alzheimer disease, etc.); (ii) hypoarousal associated with chronically low plasma glucocorticoids, which foster violence by diminishing emotional barriers that limit such behaviors (e.g. in conduct disorder and antisocial personality disorder); (iii) hyperarousal which leads to irritability and outbursts (e.g. in depression, intermittent explosive disorder, chronic fatigue, etc.). Different disorders are associated with different types of aggressiveness; e.g. hypoarousal is often associated with instrumental aggression, whereas hyperarousal is associated with uncontrollable outbursts. Many psychological disorders have been simulated in laboratory models, which were used to assess aggressiveness. Little effort was invested, however, in assessing the abnormal dimension of such aggressiveness. We present here three models that appear especially suitable to assess abnormal aspects of rodent aggression: (i) abnormal attack targeting (head, throat, and belly) that is induced by hypoarousal in rats and models violence in hypoarousal-driven human aggression (ii) 'escalated' aggression (increased aggressive response due to frustration or instigation), which models irritability and hyperarousal-driven aggressiveness; and (iii) context-independent attacks induced by hypothalamic stimulation or genetic manipulations. These three models address different aspects of abnormal aggressiveness, and can become extremely useful in three areas: in evaluating and assessing models of human psychopathologies, in studying transgenic animals, and in developing new treatment strategies. Research based on these or similar models do not address aggressiveness in quantitative terms, but follows the development of abnormal aspects, and the possibilities of their specific treatment.
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PMID:Normal and abnormal aggression: human disorders and novel laboratory models. 1648 89

Despite its frequency and high functional impact, very little is known about effective strategies for managing cognitive impairment in multiple sclerosis (MS). Disease-modifying drugs, such as beta-interferons and glatiramer acetate, may prevent or reduce the progression of cognitive dysfunction by containing the development of new cerebral lesions. To date, clinical trials have provided inconsistent results, with neuropsychological effects documented only in one trial. Moreover, pilot studies have tested symptomatic therapies for fatigue, a frequent symptom in MS, which may share a common physiopathological substrate with cognitive dysfunction. Small trials with amantadine, pemoline, 4-aminopyridine and 3-4 aminopyridine have provided mainly negative results. Acetylcholinesterase inhibitors (AChEI) used to treat Alzheimer's disease (AD)-such as donepezil, rivastigmine, and galantamine-have recently been tested in other cognitive disorders, including MS. The majority of pilot trials with AchEI in MS have provided promising results, and the donepezil study recently published by Krupp et al. represents a major development in this field. As for non-pharmacological interventions based on cognitive rehabilitation, few studies have used an experimental approach and, in general, results have been disappointingly negative. Further research is clearly needed in this area.
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PMID:Are there protective treatments for cognitive decline in MS? 1664 49

Mismatch negativity has been found to decline in amplitude with increasing age and also in Alzheimer's disease. It has been suggested that the reduction in amplitude of mismatch negativity in Alzheimer's disease is the result of fatigue rather than a generalized decline in neuronal response. We tested this hypothesis by measuring the effect of time on task on the visual mismatch negativity in both normal aging and in Alzheimer's disease. In older adults, visual mismatch negativity showed a reduction in amplitude, which did not vary with time on task. This argues against fatigue as the cause of visual mismatch negativity amplitude reduction in normal ageing. In Alzheimer's disease, visual mismatch negativity was virtually absent in responses to the first 16 deviant stimuli but present in response to subsequent deviants. This is opposite to the effect predicted by the fatigue hypothesis. It suggests that individuals with Alzheimer's disease are initially refractory to stimulus change.
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PMID:Visual mismatch negativity highlights abnormal preattentive visual processing in Alzheimer's disease. 1673 82

The objective of this update is to give an overview of the effects of dietary nutrients on the structure and certain functions of the brain. As any other organ, the brain is elaborated from substances present in the diet (sometimes exclusively, for vitamins, minerals, essential amino-acids and essential fatty acids, including omega- 3 polyunsaturated fatty acids). However, for long it was not fully accepted that food can have an influence on brain structure, and thus on its function, including cognitive and intellectuals. In fact, most micronutrients (vitamins and trace-elements) have been directly evaluated in the setting of cerebral functioning. For instance, to produce energy, the use of glucose by nervous tissue implies the presence of vitamin B1; this vitamin modulates cognitive performance, especially in the elderly. Vitamin B9 preserves brain during its development and memory during ageing. Vitamin B6 is likely to benefit in treating premenstrual depression. Vitamins B6 and B12, among others, are directly involved in the synthesis of some neurotransmitters. Vitamin B12 delays the onset of signs of dementia (and blood abnormalities), provided it is administered in a precise clinical timing window, before the onset of the first symptoms. Supplementation with cobalamin improves cerebral and cognitive functions in the elderly; it frequently improves the functioning of factors related to the frontal lobe, as well as the language function of those with cognitive disorders. Adolescents who have a borderline level of vitamin B12 develop signs of cognitive changes. In the brain, the nerve endings contain the highest concentrations of vitamin C in the human body (after the suprarenal glands). Vitamin D (or certain of its analogues) could be of interest in the prevention of various aspects of neurodegenerative or neuroimmune diseases. Among the various vitamin E components (tocopherols and tocotrienols), only alpha-tocopherol is actively uptaken by the brain and is directly involved in nervous membranes protection. Even vitamin K has been involved in nervous tissue biochemistry. Iron is necessary to ensure oxygenation and to produce energy in the cerebral parenchyma (via cytochrome oxidase), and for the synthesis of neurotransmitters and myelin; iron deficiency is found in children with attention-deficit/hyperactivity disorder. Iron concentrations in the umbilical artery are critical during the development of the foetus, and in relation with the IQ in the child; infantile anaemia with its associated iron deficiency is linked to perturbation of the development of cognitive functions. Iron deficiency anaemia is common, particularly in women, and is associated, for instance, with apathy, depression and rapid fatigue when exercising. Lithium importance, at least in psychiatry, is known for a long time. Magnesium plays important roles in all the major metabolisms: in oxidation-reduction and in ionic regulation, among others. Zinc participates among others in the perception of taste. An unbalanced copper metabolism homeostasis (due to dietary deficiency) could be linked to Alzheimer disease. The iodine provided by the thyroid hormone ensures the energy metabolism of the cerebral cells; the dietary reduction of iodine during pregnancy induces severe cerebral dysfunction, actually leading to cretinism. Among many mechanisms, manganese, copper, and zinc participate in enzymatic mechanisms that protect against free radicals, toxic derivatives of oxygen. More specifically, the full genetic potential of the child for physical growth ad mental development may be compromised due to deficiency (even subclinical) of micronutrients. Children and adolescents with poor nutritional status are exposed to alterations of mental and behavioural functions that can be corrected by dietary measures, but only to certain extend. Indeed, nutrient composition and meal pattern can exert either immediate or long-term effects, beneficial or adverse. Brain diseases during aging can also be due to failure for protective mechanism, due to dietary deficiencies, for instance in anti-oxidants and nutrients (trace elements, vitamins, non essential micronutrients such as polyphenols) related with protection against free radicals. Macronutrients are presented in the accompanying paper.
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PMID:Effects of nutrients (in food) on the structure and function of the nervous system: update on dietary requirements for brain. Part 1: micronutrients. 1706 9

Cytokine-induced sickness behavior was recognized within a few years of the cloning and expression of interferon-alpha, IL-1 and IL-2, which occurred around the time that the first issue of Brain, Behavior, and Immunity was published in 1987. Phase I clinical trials established that injection of recombinant cytokines into cancer patients led to a variety of psychological disturbances. It was subsequently shown that physiological concentrations of proinflammatory cytokines that occur after infection act in the brain to induce common symptoms of sickness, such as loss of appetite, sleepiness, withdrawal from normal social activities, fever, aching joints and fatigue. This syndrome was defined as sickness behavior and is now recognized to be part of a motivational system that reorganizes the organism's priorities to facilitate recovery from the infection. Cytokines convey to the brain that an infection has occurred in the periphery, and this action of cytokines can occur via the traditional endocrine route via the blood or by direct neural transmission via the afferent vagus nerve. The finding that sickness behavior occurs in all mammals and birds indicates that communication between the immune system and brain has been evolutionarily conserved and forms an important physiological adaptive response that favors survival of the organism during infections. The fact that cytokines act in the brain to induce physiological adaptations that promote survival has led to the hypothesis that inappropriate, prolonged activation of the innate immune system may be involved in a number of pathological disturbances in the brain, ranging from Alzheimer's disease to stroke. Conversely, the newly-defined role of cytokines in a wide variety of systemic co-morbid conditions, ranging from chronic heart failure to obesity, may begin to explain changes in the mental state of these subjects. Indeed, the newest findings of cytokine actions in the brain offer some of the first clues about the pathophysiology of certain mental health disorders, including depression. The time is ripe to begin to move these fundamental discoveries in mice to man and some of the pharmacological tools are already available to antagonize the detrimental actions of cytokines.
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PMID:Twenty years of research on cytokine-induced sickness behavior. 1708 43

In vivo molecular imaging has become a key technology for pathophysiological science and drug development. We are mostly utilizing PET(positron emission tomography) as a first-choice modality, because of its ultra-high sensitivity for molecules, adequate temporal and spatial resolution, and especially broad spectrum of target molecules. In vivo molecular imaging could bring the high-quality information about: 1. Molecular diagnosis for living patients with symptoms 2. Closer approach for etiology and differential diagnosis 3. Direct follow-up of key molecules as disease markers 4. Pharmacokinetics/Pharmacodynamics in primates/human 5. Dose finding information for individuals, corresponding to SNPs 6. Direct evidence for accumulation in non-target organs related to adverse effects 7. Drug effects with surrogate markers 8. Early decision of dropout substances (drug candidates) Here, the examples are shown as beta-amyloid imaging for Alzheimer's and mild cognitive impairment, serotonin transporter imaging for chronic fatigue, and dopaminergic components imaging for evaluation of drug for autistic spectrum disorder. In 2005, RIKEN and National Institute of Radiological Science were selected as the key centers for development of All-Japan research network to further promote mutual international and multi -disciplinary collaboration on in vivo molecular imaging.
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PMID:[Molecular imaging for drug development]. 1730 84

Deficits in cognitive function may impact one's ability to attend to stimuli, think clearly, reason, and remember. Impaired cognitive function is a common complaint among older women presenting for treatment in both mental health and medical care settings, and differential diagnosis of type and extent of cognitive impairment is important for appropriate treatment planning and prognosis. Although overall gender differences in prevalence of cognitive dysfunction are minimal, it is important when treating older women to take into account unique challenges they face in the aging process that impact the cause, type and extent of cognitive complaints with which they present in clinical settings. The current paper provides an overview to guide accurate diagnosis, particularly in women, of different types of cognitive impairment under the broad category of dementias, including Alzheimer's, Lewy Body Disease, Vascular Dementia, and due to general medical conditions such as coronary artery bypass surgery, head injury, menopause, hypothyroidism, breast cancer treatment, Fibromyalgia, and chronic fatigue. In addition, emotional factors such as depression in older female patients complicate differential diagnosis of cognitive impairment and must be addressed. Given the multiplicity of causes of cognitive difficulties for women across the life span, careful assessment is crucial; the current paper reviews assessment strategies to prepare an integrated, biopsychosocial strategy for identifying particular cognitive deficits and related psychological and medical problems. In addition, prognostic indicators and treatment planning are discussed to help the practitioner organize an empathic, reasoned and multifaceted treatment approach to maximize recovery, minimize deterioration, and manage symptoms for older women in the context of their social support system and living environment.
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PMID:Cognitive functioning and aging in women. 1758 77

Antimuscarinic drugs commonly used to treat overactive bladder are often associated with central nervous system (CNS) side effects including cognitive dysfunction, memory impairment, dizziness, fatigue, and headache. New agents show reduced CNS penetrance and better selectivity for the M3 muscarinic receptor. However, changes associated with aging may lead to alterations in blood-brain barrier permeability. Therefore, use of antimuscarinics in the elderly or in patients with Alzheimer's disease presents a significant challenge. This review highlights muscarinic receptor distribution and function in the CNS, provides a description and incidence of CNS side effects with therapy, offers information specific to currently available agents, and describes the use of antimuscarinics in special populations including children, the elderly, and patients with Alzheimer's disease.
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PMID:Antimuscarinics for the treatment of overactive bladder: a review of central nervous system effects. 1804 22


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