Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined. More recently, alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB demonstrating a neurobiological link with other "synucleinopathies" including PD and multiple system atrophy (MSA). The most significant correlates of cognitive failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in 1996, have been subjected to several validation studies against autopsy findings. These conclude that although diagnostic specificity is high (range 79- 100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved methods of case detection are therefore required. Fluctuating impairments in attention, visual recognition and construction are more indicative of DLB than AD. Relative preservation of medial temporal lobe volume on structural MRI and the use of SPECT tracers for regional blood flow and the dopamine transporter are the most reliable current biomarkers for DLB. There are no genetic or CSF tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all elderly demented cases reaching autopsy have DLB, making it the most common cause of degenerative dementia after AD. Exquisite, not infrequently fatal, sensitivity to neuroleptic drugs and encouraging reports of the effects of cholinesterase inhibitors on cognitive, psychiatric and neurological features, mean that an accurate diagnosis of DLB is more than merely of academic interest. Dementia developing late in the course of PD shares many of the same clinical and pathological characteristics.
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PMID:Dementia with Lewy bodies. 1256 32

Cocaine abuse is a serious health problem in many areas of the world, yet there are no proven effective medications for the treatment of cocaine dependence. Preclinical studies suggest that the reinforcing effect of cocaine that promotes its abuse is mediated by blockade of the presynaptic dopamine transporter. This results in increased dopamine activity in the mesolimbic or meso-accumbens dopamine reward system of brain. Development of new medications to treat cocaine dependence has focused on manipulation of this dopamine system, either by direct action on dopamine binding sites (transporter or receptors) or indirectly by affecting other neurotransmitter systems that modulate the dopamine system. In principle, a medication could act via one of three mechanisms: (i) as a substitute for cocaine by producing similar dopamine effects; (ii) as a cocaine antagonist by blocking the binding of cocaine to the dopamine transporter; or (iii) as a modulator of cocaine effects by acting at other than the cocaine binding site. The US National Institute on Drug Abuse has a Clinical Research Efficacy Screening Trial (CREST) programme to rapidly screen existing medications. CREST identified four medications warranting phase II controlled clinical trials: cabergoline, reserpine, sertraline and tiagabine. In addition, disulfiram and selegiline (deprenyl) have been effective and well tolerated in phase II trials. However, selegiline was found ineffective in a recent phase III trial. Promising existing medications probably act via the first or third aforementioned mechanisms. Sustained-release formulations of stimulants such as methylphenidate and amfetamine (amphetamine) have shown promise in a stimulant substitution approach. Disulfiram and selegiline increase brain dopamine concentrations by inhibition of dopamine-catabolising enzymes (dopamine-beta-hydroxylase and monoamine oxidase B, respectively). Cabergoline is a direct dopamine receptor agonist, while reserpine depletes presynaptic stores of dopamine (as well as norepinephrine and serotonin). Sertraline, baclofen and vigabatrin indirectly reduce dopamine activity by increasing activity of neurotransmitters (serotonin and GABA) that inhibit dopamine activity. Promising new medications act via the second or third aforementioned mechanisms. Vanoxerine is a long-acting inhibitor of the dopamine transporter which blocks cocaine binding and reduces cocaine self-administration in animals. Two dopamine receptor ligands that reduce cocaine self-administration in animals are also undergoing phase I human safety trials. Adrogolide is a selective dopamine D(1) receptor agonist; BP 897 is a D(3) receptor partial agonist.A pharmacokinetic approach to treatment would block the entry of cocaine into the brain or enhance its catabolism so that less cocaine reached its site of action. This is being explored in animals using the natural cocaine-metabolising enzyme butyrylcholinesterase (or recombinant versions with enhanced capabilities), catalytic antibodies, and passive or active immunisation to produce anti-cocaine binding antibodies. A recent phase I trial of a "cocaine vaccine" found it to be well tolerated and producing detectable levels of anti-cocaine antibodies for up to 9 months after immunisation.
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PMID:Agents in development for the management of cocaine abuse. 1523 92

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.
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PMID:Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. 1668 91

The diagnosis of dementia with Lewy bodies (DLB) is difficult if one relies solely on clinical features. Current International Consensus Criteria for DLB have high specificity but a significant percentage of patients might be misdiagnosed. Reasons for clinical uncertainty regard the presence of concomitant motor signs in patients with Alzheimer's disease as well as the observation that cognitive abnormalities in DLB might develop with memory impairment without significant parkinsonism. This has clinical relevance as DLB patients may be particularly sensitive to antipsychotics and even the effectiveness of atypical neuroleptics such as quetiapine for the treatment of agitation and hallucinations has been questioned by double-blind, placebo-controlled, randomized studies. By contrast, acetyl-cholinesterase inhibitors such as rivastigmine have shown benefit not only on cognitive but also on psychiatric symptoms. Recent evidence shows that striatal dopamine transporter binding of (123)I-ioflupane SPECT is reduced in DLB and this is consistent with a significant loss of nigral dopamine neurons in this disorder. Several studies have demonstrated the diagnostic accuracy of (123)I-ioflupane in the differential diagnosis of parkinsonism. Given the availability of SPECT, this investigation represents a useful marker to support clinical diagnosis and can help establishing appropriate treatment for this disorder.
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PMID:The role of I-ioflupane SPECT dopamine transporter imaging in the diagnosis and treatment of patients with dementia with Lewy bodies. 1930 May 62

Diffuse Lewy body disease, also called dementia with Lewy bodies (DLB), is defined as progressive dementia and pathological Lewy bodies distributed in the central and autonomic nervous systems. The clinical features are dementia, cognitive fluctuations, visual hallucinations, parkinsonism, and REM sleep behavior disorder (RBD). Confirmatory techniques include dopamine transporter imaging, meta-iodobenzylguanidine (MIBG) myocardial scintigraphy, and polysomnography. The pathology finding in DLB is misfolded alpha-synuclein, the main component of Lewy bodies, propagating in the central nervous system. This may interrupt the acetylcholine pathway and activate an inflammatory response. Mutations of several genes have been found in patients with DLB, including SNCA, GBA, and APOE. The differential diagnosis of DLB and Parkinson's disease with dementia (PDD) is a debated issue. Clinical features distinguishing DLB from PDD include the timing of dementia and visual hallucinations, responses to dopaminergic agents and anti-psychotics, and imaging findings. As to the management of DLB, cholinesterase inhibitors are the Level-A recommendation for treating dementia in DLB patients and also are beneficial for treating visual hallucinations and psychotic symptoms. Dopamine agonists have the risk of inducing psychotic symptoms, while levodopa should be used carefully for motor symptoms. Melatonin and clonazepam are effective in controlling RBD. Several other treatment methods are undergoing trials, including pimavanserine, nilotinib, psychological interventions, and behavior therapy.
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PMID:Diffuse Lewy body disease. 3080 82

Acute presentations for dementia, particularly dementia with Lewy bodies (DLB), are rare and can pose diagnostic challenges.We present a case of a 75-year-old woman who was previously fit, well and independent in all activities of daily living. She had no history of psychiatric, cognitive or memory problems. She presented with 2 weeks of sudden onset confusion, paranoia, dizziness and reduced oral intake. Thorough investigations for causes of delirium including blood tests, cerebrospinal fluid analysis obtained via lumbar puncture, electroencephalography, computed tomography, and magnetic resonance imaging were within normal limits. Further neurological examination demonstrated she had subtle Parkinsonian signs (cogwheel rigidity, bradykinesia) and was hypersensitive to small doses of antipsychotic (haloperidol and risperidone). A positive dopamine transporter scan was done confirming a diagnosis of an acute presentation of DLB. She has been commenced on a cholinesterase inhibitor (rivastigmine) and is presently settled in care.
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PMID:Acute presentation of dementia with Lewy bodies. 3153 Jul 7

Dementia with Lewy bodies (DLB) is the second most common form of dementia in the elderly, and various clinical symptoms, including olfactory dysfunction, dysautonomia, depression, and rapid eye movement sleep behavior disorders (RBD), occur in patients with the prodromal state of DLB. We herein describe a case of a 72-years-old right-handed woman who exhibited primary progressive aphasia (PPA) as a prodromal state of DLB and took cholinesterase inhibitors (donepezil). At 4.5 years after aphasia onset, she exhibited all the core clinical features of DLB, including visual hallucinations, fluctuating cognition, RBD, and Parkinsonism, as well as progressive language impairment. She showed reduced dopamine transporter (DAT) uptake (assessed by DAT single-photon emission computed tomography imaging) in the striatum and decreased cardiac uptake (determined by 123I-metaiodobenzylguanidine myocardial scintigraphy), which are indicative biomarkers of DLB. Thus, this patient met all the criteria for probable DLB. Notably, the unique feature of this case was the presentation of PPA, which is seldom observed in typical DLB. Moreover, cholinergic enhancement (donepezil, 5 mg daily) improved her language function and global cognitive function, although mild aphasia remained. The findings provide valuable insights into the spectrum of the prodromal state of DLB and shed light on the development of the medication for PPA caused by cholinergic insufficiency.
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PMID:Primary Progressive Aphasia as a Prodromal State of Dementia With Lewy Bodies: A Case Report. 3213 65