Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis of amyotrophic lateral sclerosis (ALS) remains obscure, but it is now clear that neuronal loss is not confined to the motor cortex, even in cases without dementia. A reliable method of assessing cortical involvement in vivo remains elusive. WAY100635 binds selectively to the 5-hydroxytryptamine (5-HT1A) receptor, which is expressed on pyramidal neurones present throughout the cortex. [11C]-WAY100635 PET is, therefore, a potential marker of cerebral neuronal loss or dysfunction in ALS. Twenty-one ALS subjects and 19 healthy volunteers underwent [11C]-WAY100635 PET of the brain. A cortical template consisting of multiple volumes of interest (VOI) was applied to each individual's [11C]-WAY100635 binding potential (BP) image to determine the regional reduction in binding in ALS patients compared to controls. There was a marked reduction (21%) in both the global cortical and raphe BP of [11C]-WAY100635 in ALS patients (P < 0.001), with regional variations in the VOI analysis that ranged from 16% to 29% decrease compared with the control group, and trends to greater reductions in those with bulbar involvement. To clarify the significance of the global cortical reductions, statistical parametric mapping was used as an alternative method to identify the cortical regions with the most significant decreases in [11C]-WAY100635 binding. SPM analysis revealed the greatest differences between ALS cases and controls in frontotemporal regions, cingulate and lateral precentral gyri. The reductions in cortical [11C]-WAY100635 binding were not related to depression, riluzole or other drug use. We postulate that the reduction of 5-HT1A binding represents loss of, or damage to, neurones bearing these receptors although we cannot exclude the possibility that these reductions reflect alterations in receptor expression or function. Further investigation into the role of the 5-HT1A receptor and the potential of [11C]-WAY100635 PET as a marker of cortical dysfunction in ALS is warranted.
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PMID:[11C]-WAY100635 PET demonstrates marked 5-HT1A receptor changes in sporadic ALS. 1568 56

The determinants of ALS caregiver burden and the feeling of the patients as being a burden were assessed using the Caregiver Burden Inventory and the Self-Perceived Burden Scale in 60 caregiver-patient couples. Caregiver burden was correlated to their level of depression and quality of life and, differently from other chronic disorders, increased with the worsening of patients' disability. ALS patients have a good objective perception of their impact on caregivers.
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PMID:Caregiver burden and patients' perception of being a burden in ALS. 1591 11

Amyotrophic lateral sclerosis (ALS) is a fatal disease, leaving the patient in a partially or completely deafferented state. In an explorative study, we investigated responses to visual socio-emotional stimuli in ALS patients. Pictures from the International Affective Picture System (IAPS) were verbally judged by 12 moderately affected ALS patients with a spinal onset and a slow progression and 18 age-matched controls, and data were compared with psychophysiological responses. Verbal emotional judgments of patients were more positive than ratings of controls. Regarding arousal, patients neutralized extreme pictures, in that they rated calm pictures as more exciting than controls and exciting pictures as more calm. These changes of emotional processing were unrelated to depression or frontal lobe dysfunction. There were no major differences between patients and controls concerning physiological responses to emotional stimuli. We conclude that emotional responses of ALS patients tend to be altered towards positive valence and towards a more balanced arousal state in early stages of the disease. These findings contradict assumptions of a generally negative impact of the disease on the emotional disposition and may indicate compensatory cognitive or neuroplastic changes.
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PMID:Emotional responding in amyotrophic lateral sclerosis. 1597

The objective of this study was to identify prognostic factors for survival in amyotrophic lateral sclerosis from a large prospective observational study performed in France. The study included a cohort of 2069 patients fulfilling broad entry criteria treated with riluzole. Over 100 demographic, biological, clinical and quality-of-life variables were monitored and assessed for their effect on survival. Patients were randomized post hoc into two groups: one group (two-thirds of the patients) to generate the prognostic models and one group (one-third of the patients) to validate the resulting models. Thirteen variables were found to affect survival independently and were used to construct a survival prediction score, RL401. These included age, disease duration, slow vital capacity, intensity of tiredness (visual analogue scale), number of body levels with spasticity, atrophy and/or fasciculations, cough, distal muscle strength, household income, depression and two biological parameters, plasma creatinine levels and neutrophil counts. A simplified score, RL401S, was constructed, designed to be easy to use and interpret. The predictive powers of the two scores were similar.
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PMID:Prognostic factors for survival in amyotrophic lateral sclerosis patients treated with riluzole. 1603 24

Considering the few studies published on the psychopathology of ALS patients, we carried out a preliminary study evaluating depression, anxiety, emotional reactions and coping strategies in such patients. Twenty-seven ALS patients were included and evaluated using a semi-structured interview, after which they were asked to complete a questionnaire. The rater asessed the DSM-IV criteria for a major depressive episode, dysthymia and generalized anxiety, using the MADRS scale for depression, the Covi anxiety scale and the Depressive Mood scale. Subsequently, patients completed the Ways of Coping checklist. Patients were neither anxious nor depressed. Patients whose diagnosis was recent (less than six months) presented greater emotional deficit. Patients younger than 50 years of age used problem focused strategies more frequently. Those having received the diagnosis in the preceeding six months used emotion focused strategies significantly more often.The absence of characterized depression and anxiety confirmed results of the literature. The significance of this study is found in the observation of specific emotional reactions present in the first six months following diagnosis disclosure. The results show that it is useful to continue the affective evaluation of these patients and to undertake longitudinal studies starting at the time of diagnosis disclosure.
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PMID:Psychopathology in amyotrophic lateral sclerosis: a preliminary study with 27 ALS patients. 1631 25

The S100B is a Ca2+ binding proteins of EF-hand type and is produced primarily by astrocytes in the central nervous system. This protein has been implicated in the Ca2+-dependent regulation of a variety of intracellular functions such as protein phosphorylation, enzyme activities, cell proliferation and differentiation, dynamics of cytoskeleton constituents, structural organization of membranes, intracellular Ca2+ homeostasis, inflammation, and protection from oxidative cell damage. Recent studies suggest that released S100B exerts paracrine and autocrine effects on neurons and glia. On the other hand, elevations of S100B levels in blood or cerebrospinal fluid have been observed in patients with Alzheimer's disease, Down's syndrome, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia, depression, cerebral stroke and traumatic brain injury, and the levels have reached micromol/L-order at focal regions. It has been documented that the excessive S100B promotes the expression of inducible nitric oxide synthase or pro-inflammatory cytokines and exhibits detrimental effects on neurons. On studies using some animal models of the cerebral stroke or Alzheimer's disease, it is suggested that the excessive S100B produced by activated astrocytes precedes neurodegenerations. Authors discussed the relationship between neurological disorders and the S100B.
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PMID:[S100B: astrocyte specific protein]. 1663 91

Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels. They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memory-related signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors. On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation. NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimer's and Parkinson' disease, depression, epilepsy, trauma and stroke to schizophrenia. This fundamental significance of NMDA receptor-related excitotoxicity is discussed in the context of the developing clinical success of Memantine, but moreover set into relation to various proteomic and genetic markers of said diseases. The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD). The flexibility and multitude of interaction partners and possibilities of these highly dynamic molecular systems are discussed in terms of drug development strategies, in particular comparing high affinity and sub-type specific ligands to currently successful or promising therapies.
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PMID:NMDA receptors are not alone: dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate-signalling. 1671 8

We sought to characterize ALS patients who opt for tracheostomy and long-term mechanical ventilation (LTMV) and compare them with respect to medical, psychiatric, and psychosocial measures to patients who declined tracheostomy and died. We studied 72 ALS patients who were identified as hospice-eligible. They were assessed monthly until the endpoint of death or tracheostomy. LTMV patients continued to be followed for up to 55 months. The spouse or other caregiver was similarly interviewed and followed. Medical and psychiatric evaluations were conducted, in addition to self-reported depressive symptoms, future orientation, attitudes about hastened death, religious beliefs, and quality of life. Global cognitive capacity was assessed by caregivers. Fourteen patients chose LTMV; 58 died without LTMV. At study entry, those who later chose LTMV were younger, more had young children, had more education, and higher household incomes on average. Although their physical conditions were similar, they reported higher levels of optimism including belief in imminent cure, and more positive appraisals of their ability to function in daily life, their physical health and overall life satisfaction. At study entry, none who later chose LTMV were clinically depressed, compared to 26% of those who later refused LTMV, and their mean scores on the Beck Depression Inventory were in the "not depressed" range while the mean for patients who later died was in the "probable depression" range. Fourteen percent of patients who later chose LTMV were reported by caregivers to have had at least mild cognitive problems, compared to 49% of those who later died. After an average of 33 months on LTMV, only about half retained high levels of optimism and enjoyment of daily life, independent of residence (home vs. facility). Two patients expressed interest in hastening death but none had asked to terminate ventilation despite disease progression. However, half identified future circumstances that would render life intolerable. At last contact with caregivers, only one LTMV patient was reported to have major cognitive impairment. While reporting substantial emotional burden after LTMV, most but not all spousal caregivers continued to express satisfaction with care-giving. Our findings suggest that the choice of LTMV was not about desperation (although it may involve unrealistic expectations of cure by some), ignorance, or inability to make wishes clear during a chaotic dying period. Rather, LTMV choice was consistent with a sustained sense that life was worth living in any way possible, at least for some time and within certain boundaries. ALS clinicians will need to recognize this motivation and provide appropriate clinical education to both patient and family.
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PMID:Predictors and course of elective long-term mechanical ventilation: A prospective study of ALS patients. 1675 72

The neurotrophins-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3 and NT-4-represent a family of proteins essential for neuronal survival and plasticity. Each neurotrophin can signal through two different transmembrane receptors, Trk receptor tyrosine kinases and the p75 neurotrophin receptor, the first member of the TNF receptor superfamily. Neurotrophic factors play an important role in neurodegenerative diseases, as well as neuropsychiatric disorders such as depression, bipolar disease and eating disorders. Indeed, a number of approaches have been taken to use neurotrophins to treat Alzheimer's dementia, amyotrophic lateral sclerosis and peripheral sensory neuropathy. However, many of these clinical trails have failed, due to problems in delivery and unforeseen side effects of neurotrophic factors. An alternative approach is to use ligands in the G protein-coupled receptor (GPCR) family to transactivate trophic activities. We have discovered that treatment with adenosine, a neuromodulator that acts through G protein-coupled receptors, is capable of activating Trk tyrosine kinase receptors. Transactivation of neurotrophic receptors by GPCR ligands raise the possibility that small molecules may be used to elicit neurotrophic effects for the treatment of neurodegenerative diseases. This approach would allow for selective targeting of neurons that express specific G protein-coupled receptors and trophic factor receptors. GPCRs transduce information provided by extracellular signals to modulate synaptic activity and neurotransmission. In addition to the classical G protein signalling, GPCR ligands also activate receptor tyrosine kinases (RTK), including neurotrophin receptors. Activation of Trk neurotrophin receptors can occur by GPCR ligands in the absence of neurotrophins. Adenosine and PACAP (pituitary adenylate cyclase activating polypeptide) induce Trk activation specifically through their respective GPCRs to promote cell survival. Transactivation of Trks by GPCRs has emerged as a new theme in the biology of neurotrophin function. Although the precise role of transactivation is unknown, one possibility is that it adds a safety factor that might protect neurons from death in the absence of neurotrophins. Abnormal activity of the neurotrophin system has been implicated in several psychiatric and neurobiological illnesses. However, the lack of knowledge about the precise site of neurotrophin dysfunction has compromised the ability to improve the efficacy and the safety of drugs used in treatment modalities. If small-molecule GPCR ligands can ameliorate neuronal cell loss through Trk, transactivation may offer a new strategy for promoting trophic effects during neurodegeneration.
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PMID:Promoting neurotrophic effects by GPCR ligands. 1680 30

During the past decade, numerous molecular mediators of neurodegenerative diseases and neurological disorders have been identified and validated, yet few novel therapies have emerged and the unmet medical needs remain high. These molecular mediators belong to target classes such as ion channels, neurotransmitters and neurotransmitter receptors, cytokines, growth factors, enzymes and other proteins. In some cases, substantial pre-clinical validation exists, but the molecular target has not been readily druggable with small molecules, proteins or antibodies. RNA interference represents a therapeutic approach applicable to such non-druggable targets. Both non-viral and viral delivery strategies are being undertaken for in vivo silencing of molecular targets by RNA interference, which has resulted in robust efficacy in animal models of Alzheimer's disease, ALS, Huntington's disease, spinocerebellar ataxia, anxiety, depression, neuropathic pain, encephalitis and glioblastoma. These proof-of-concept data in animal models, together with the commencement of clinical trials using RNA interference for macular degeneration and respiratory syncytial virus infection, point to the potential of direct RNA interference for neurological disorders and neurodegenerative diseases.
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PMID:Therapeutic potential of RNA interference for neurological disorders. 1681 77


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