Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atypical antipsychotics will continue to be prescribed for the behavioral symptoms of dementia in the absence of more effective, better tolerated, and safer alternatives. The evidence base, although incomplete, suggests that modest treatment effect sizes are offset by risk of considerable adverse effects. How might this information be best applied to clinical practice? Non-pharmacologic strategies should be implemented in routine clinical practice. Placebo-controlled clinical trials of individual antipsychotic agents have historically reported high placebo response rates; CATIE-AD reported that the sum total of the risk/benefit equation of atypical antipsychotic therapy was no greater than that achieved by placebo. CATIE-AD was designed to study the effectiveness of atypical antipsychotic treatment in community dwelling patients with AD. It is uncertain whether the results can be generalized to the populations of dementia patients residing in nursing homes with more severe cognitive and behavioral impairment. There is some suggestion that nursing home patients with dementia complicated by severe behavioral symptoms, particularly agitation and aggression without accompanying psychosis, might achieve greater benefit from atypical antipsychotic treatment than patients with milder behavioral symptoms. The finding that dementia patients without psychosis may respond more robustly to antipsychotic treatment seems counterintuitive, but may support the hypothesis that the neurobiology of the "psychosis of AD" differs from the psychosis of schizophrenia or bipolar disease. Adverse effects associated with antipsychotic therapy should be aggressively monitored throughout therapy. Treatment-emergent sedation was associated with all of the atypical antipsychotics in CATIE-AD and is probably an important mediator of mortality risk in patients with dementia. Sedation exacerbates pre-existing cognitive impairment and increases the risk of complications such as aspiration pneumonia, so concomitant use of benzodiazepines should be discouraged or limited to short periods with careful observation.' Once initiated, the effectiveness and tolerability of antipsychotic therapy should be evaluated routinely. In Alzheimer's disease, the severity and frequency of behavioral symptoms often decreases as illness progresses. In a stable patient, it is prudent to attempt to taper and discontinue the antipsychotic after 2-8 months of therapy. Better understanding of the potential adverse effects of antipsychotic therapy has increased interest in the effects of the dementia-specific medications on behavioral symptoms. Reductions in neuropsychiatric symptoms have been reported from trials of individual cholinesterase inhibitors, memantine monotherapy, and memantine combined with donepezil in AD patients. Studies of small numbers of patients in open trials of cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and one double-blind placebo controlled trial (rivastigmine) have reported varying degrees of improvement of behavioral symptoms and psychosis of dementia with Lewy bodies (DLB). Delusions, hallucinations, apathy, and agitation/aggression are cited as the symptom categories most likely to show significant improvement. Since few of these studies were prospectively designed to study behavioral symptoms, results must be interpreted cautiously. Treatment of behavioral symptoms in AD and other dementias is challenging. The limitations of current approaches drive the search for effective, well tolerated therapies.
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PMID:Atypical antipsychotics for the treatment of dementia-related behaviors: an update. 1763 94

Nicotinic acetylcholine receptor (nAChR) dysfunction occurs in individuals with schizophrenia (SZ) and may also affect individuals with bipolar disorder (BP). The molecular mechanisms for these disease-associated cholinergic deficits are not known. In vitro, the protein RIC-3 (resistance to inhibitors of cholinesterase-3) aids the assembly and trafficking of alpha7-nAChRs but has unclear action on the biogenesis of alpha4/beta2-nAChRs. To evaluate RIC-3/nAChR dynamics in diseased and normal human brain tissue, we measured RIC-3, alpha7-, alpha4- and beta2-nAChRs transcript levels in postmortem prefrontal cortex of individuals with SZ (n=31), BP (n=28) and unaffected controls (NC, n=33). Of the 28 individuals with BP, 20 had a history of psychotic symptoms. We compared relative message abundances between diagnostic groups and tested correlations of RIC-3 with each nAChR message subtype. RIC-3 and alpha4 messages were significantly increased in BP compared with NC (RIC-3, P< or =0.002; alpha4, P< or =0.04). RIC-3 message was also upregulated in SZ (P< or =0.04). In BP with psychoses, RIC-3 and alpha4 levels were increased compared with BP without psychoses (both P< or =0.02) and compared with NC (RIC-3, P< or =0.0003; alpha4, P< or =0.004). In correlation regression analyses, RIC-3 expression was very highly correlated to alpha7, alpha4 and beta2 in NC (alpha7, P< or =2.5e-05; alpha4, P< or =2.5e-09; beta2, P< or =0.003) and in SZ (alpha7, P< or =1e-07; alpha4, P< or =7e-07; beta2, P< or =3e-09). RIC-3 also strongly correlated with alpha7 and alpha4 in BP (alpha7, P< or =0.003; alpha4, P< or =3.5e-07). RIC-3 was modestly correlated with beta2 in BP overall (P< or =0.04), but showed no significant correlation in BP with psychoses (P< or =0.31) compared with a significant correlation in BP without psychoses (P< or =0.007). In conclusion, coordinated RIC-3/alpha4 upregulation and discordant RIC-3/beta2 levels suggest that alpha4/beta2 nAChR deficits in BP may occur from dysregulated RIC-3 chaperoning of the beta2 nAChR subunit in a subset of patients affected by psychotic features.
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PMID:Lack of RIC-3 congruence with beta2 subunit-containing nicotinic acetylcholine receptors in bipolar disorder. 1764 Aug 15

Alzheimer's disease (AD) is the most common cause of dementia affecting nearly 18 million people around the world and 4.5 million in the US. It is a progressive neurodegenerative condition that is estimated to dramatically increase in prevalence as the elderly population continues to grow. As the cognitive and neuropsychiatric signs and symptoms of AD progresses in severity over time, affected individuals become increasingly dependent on others for assistance in performing all activities of daily living. The burden of caring for someone affected by the disorder is great and has substantial impact on a family's emotional, social and financial well-being. In the US, the currently approved medications for the treatment of mild to moderate stages of AD are the cholinesterase inhibitors (ChEIs). Cholinesterase inhibitors have shown modest efficacy in terms of symptomatic improvement and stabilization for periods generally ranging from 6 to 12 months. There are additional data that have emerged, which suggest longer-term benefits. For the moderate to severe stages of AD, memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist is in widespread use and has shown modest benefit as monotherapy and in combination with ChEIs. The cost effectiveness of the currently available therapeutic agents for AD has undergone great scrutiny and remains controversial, especially outside the US. Neuropsychiatric symptoms such as agitation and psychosis are common in AD. Unfortunately, in the US there are no Food and Drug Administration (FDA)-approved agents for the treatment of these symptoms, although atypical antipsychotics have shown some efficacy and have been widely used. However, the use of these agents has recently warranted special caution due to reports of associated adverse effects such as weight gain, hyperlipidemia, glucose intolerance, cerebrovascular events, and an increased risk for death. Alternative agents used to treat neuropsychiatric symptoms include serotonergic antidepressants, benzodiazepines, and anticonvulsant medications.
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PMID:Treatment of Alzheimer's disease across the spectrum of severity. 1804 10

The authors review current literature on hallucinations in Parkinson's disease (PD). Recent neuropathological studies showed that hallucinations occur in synucleinopathies and are a significant predictor of Lewy Body depositions. Therefore, hallucinations are a hallmark of PD and of dementia with Lewy Bodies. Visual hallucinations are mostly complex and kinematic; preserved or disturbed insight on the nature of hallucinations is a major prognostic factor, although eventually all hallucinators will present with reduced insight. Current theories on the origin of hallucinations point to visual dysfunction, dream overflow and cognitive impairment, yet objection can be raised on each one of the putative models of hallucinations. Understanding of the origin of hallucinations is required in order to develop treatments: all treatment evaluations were focused in general on psychosis, and only clozapine obtained positive evidence-based ratings on efficacy. However, it is likely that cholinesterase inhibitors, antipsychotics and anti-5-hydroxytryptamine(3) agents and drugs acting on sleep regulation will have different and perhaps opposite effects on different types of hallucinations, whether they are accompanied by disturbed insight, sleep disorders or other psychotic features. Further studies will try to separate phenomenology and responses to treatment and will investigate the relevance of concomitant sleep disorders and abnormality of frontoparietal networks involved in the attention process.
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PMID:New approaches to understanding hallucinations in Parkinson's disease: phenomenology and possible origins. 1805 66

Diagnosis and treatment of dementia in nursing homes and assisted living facilities remains challenging since response to treatment and disease course varies for the common degenerative dementias. Four cholinesterase inhibitors and an N-methyl-D-aspartate glutamate receptor antagonist are approved by the US Food and Drug Administration for the treatment of Alzheimer's disease (AD). Treatment with AD medications is clinically efficacious and associated with reduced caregiver burden. Some controlled trials have reported that cholinesterase inhibitors and memantine ameliorate dementia-related behavioral symptoms. Antipsychotic therapy is often used for intractable behavioral symptoms or psychosis not responding to nonpharmacologic interventions and antidementia medications; however, the risk/benefit ratio for each patient should be critically evaluated, because treatment with atypical antipsychotics has been associated with serious adverse events, including increased risk for death in older adults with dementia.
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PMID:Current issues in dementia pharmacotherapy. 1809 83

Mitochondrial disorders, in particular respiratory chain diseases (RCDs), present either as single organ problem or as multi-system disease. One of the most frequently affected organs in RCDs, in addition to the skeletal muscle, is the central nervous system (CNS). CNS manifestations of RCDs include epilepsy, stroke-like episodes, migraine-like headache, ataxia, spasticity, movement disorders, psychosis, demyelination, calcification, but also dementia. Cognitive impairment may be a feature of syndromic as well as non-syndromic RCDs. Syndromic RCDs associated with cognitive impairment include MELAS, KSS, Leigh syndrome, and many others. RCDs with cognitive decline not only result from mtDNA mutations but also from mutations in nuclear genes. At onset there is often no general intellectual deterioration in these patients but specific cognitive deficits, particularly in the visual construction, attention, abstraction, or flexibility. Diagnosis of cognitive impairment from RCDs is based on neuropsychological testing, imaging studies, including MRI, PET, SPECT, or MR-spectroscopy, CSF investigations, or electroencephalography. Therapeutic strategies for dementia in RCDs rely on symptomatic measures. Only single patients may profit from cholinesterase inhibitors or memantine, antioxidants, vitamins, or other substitutes. Overall, cognitive decline in RCDs (mitochondrial dementia) needs to be included in the differentials of dementia.
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PMID:Cognitive decline as a manifestation of mitochondrial disorders (mitochondrial dementia). 1857 95

Visual hallucinations are a typical feature of Lewy body parkinsonism and occur in some 40% of patients with Parkinson's disease. Age and cognitive decline are the most important intrinsic risk factors, but hallucinosis is often triggered by comorbid conditions such as infection and dehydration. The single most important trigger, however, is exposure to CNS drugs, in particular antiparkinsonian agents. While hallucinosis and psychosis can be triggered by amantadine and anticholinergics, they are more commonly experienced after changes in dopaminergic medication. Dopamine agonists have greater potential to induce hallucinosis compared with L-dopa. Attempting to reduce antiparkinsonian drugs is an important part in the management of these patients, but atypical neuroleptics like clozapine or quetiapine are frequently necessary. Visual hallucinations in Parkinson's disease patients with dementia can also be improved by treatment with the cholinesterase inhibitor rivastigmine.
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PMID:When a Parkinson's disease patient starts to hallucinate. 1864 10

Parkinson's disease (PD) is characterized by its motor impairment. However, non-motor symptoms such as psychiatric disorders, autonomic disturbances and sleep disorders frequently complicate the course of the disease. In particular, psychiatric disturbances including cognitive impairment, depression and psychosis impact these patients considerably. Approximately 31 % of PD patients suffer from cognitive impairment and dementia. Currently, two different clinical presentations are distinguished in PD patients, who present with dementia: Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), which are two different presentations of a single underlying disease process leading to the deposition of alpha-synuclein. Clinically, PDD is distinguished from DLB alone by the different temporal manifestations of extrapyramidal motor symptoms. Dementia is characterized by a subtle onset and progressive cognitive decline with a predominant dysexecutive syndrome, which can be accompanied by different behavioral symptoms such as hallucinations, depression, anxiety and sleep disorders. Dysregulation of different neurotransmitters has been associated with cognitive decline, but reduced cholinergic transmission is currently thought to be the pivotal mechanism in the development of cognitive dysfunction. Therefore, cholinesterase inhibitors are used in the treatment of dementia and accompanying behavioral symptoms in PDD and DLB. The occurrence of dementia impacts not only the patients themselves but also their care-givers and family.This article focuses on the clinical issues related to both disorders and is based on a meeting of experts which took place in April 2008 in Dresden.
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PMID:Lewy body dementia and Parkinson's disease with dementia. 1878 81

Dementia with Lewy bodies (DLB), the second most frequent cause of dementia after Alzheimer disease (AD), is characterized by the widespread distribution of Lewy bodies in virtually every brain area. Clinically, DLB is distinguished from AD by fluctuating cognition, prominent visual hallucinations and parkinsonism, and from Parkinson disease, by the appearance of parkinsonism within one year of cognitive or behavioral decline. The main component of Lewy bodies is alpha-synuclein. Accumulating evidence suggests that its aggregation constitutes one of the first steps preceding Lewy body formation, so that antiaggregation strategies would be very useful to prevent alpha-synuclein fibril formation. Main therapies nevertheless applied up to the present remain symptomatological. In this context, cholinesterase inhibitors such as rivastigmine, galantamine and donepezil, are used for the treatment of delusions and other psychotic symptoms. This review focuses on the recent discovery of possible alpha-synuclein anti-aggregation factors, where four main classes can be defined. First, beta-synuclein as well as alpha-synuclein derived peptides in addition to antibodies present a group of proteins and peptides that directly interact with alpha-synuclein and so inhibit its aggregation. Second, small molecules interfere with alpha-synuclein aggregation by their covalent binding, although not all of them are suitable for an appropriate inhibition of alpha-synuclein aggregation. Third, to inhibit the expression of alpha-synuclein and its isoforms at the RNA level, the use of interference RNA represents a future challenge. The fourth strategy is based on the enhancement of inclusion body formation to accelerate the elimination of soluble alpha-synuclein oligomers. Each chapter section includes the discussion of possible strategies for the development of drugs and therapies.
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PMID:The therapeutical potential of alpha-synuclein antiaggregatory agents for dementia with Lewy bodies. 1899 34

Although idiopathic Parkinson disease (PD) remains the only neurodegenerative disorder for which there are highly effective symptomatic therapies, there are still major unmet needs regarding its long-term management. Although levodopa continues as the gold standard for efficacy, its chronic use is associated with potentially disabling motor complications. Current evidence suggests that these are related to mode of administration, whereby multiple oral doses of levodopa generate pulsatile stimulation of striatal dopamine receptors. Current dopamine agonists, while producing more constant plasma levels, fail to match levodopa's efficacy. Strategies to treat levodopa-related motor complications are only partially effective, rarely abolishing motor fluctuations or dyskinesias. Best results are currently achieved with invasive strategies via subcutaneous (s.c.) or intraduodenal delivery of apomorphine or levodopa, or deep brain stimulation of the subthalamic nucleus. Another area of major unmet medical need is related to nondopaminergic and nonmotor symptoms of PD. Targeting transmitter systems beyond the dopamine system is an interesting approach, both for the motor and nonmotor problems of PD. So far, clinical trial evidence regarding 5-HT agonists, glutamate antagonists, adenosine A(2) antagonists and alpha-adrenergic receptor antagonists, has been inconsistent, but trials with cholinesterase inhibitors and atypical antipsychotics to treat dementia and psychosis, have been successful. However, the ultimate goal of PD medical management is modifying disease progression, thereby delaying the evolution of motor and nonmotor complications of advanced disease. As understanding of preclinical markers for PD develops, there is new hope for neuropreventive strategies to target "at risk" populations before clinical onset of disease.
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PMID:Treatments for Parkinson disease--past achievements and current clinical needs. 1922 17


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