Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the more recently recognized problems in treatment of patients with Parkinson's disease (PD) is development of cognitive dysfunction and, in many cases, frank dementia. As patients with PD live longer, because of improved care and treatment of motor symptoms, dementia in PD is becoming a major contributor to morbidity in the illness. Prevalence studies suggest that up to 30% of patients with PD develop dementia. Dementia in PD patients is often a multifactorial condition. Neuropathologic changes caused by PD itself may cause memory loss. However, some patients with PD and memory decline also have pathologic changes that are more consistent with Alzheimer's disease. Many PD patients have a mix of the two types of pathology. Other factors, such as underlying illnesses, medication side effects, and interaction of therapeutic agents, may contribute to cognitive changes in PD patients. Predictors of development of dementia in PD include advancing age and severity of neurologic symptoms, which may interact with one another to produce this effect. Recent work suggests that tobacco use also may increase risk of PD dementia, despite its possible protective effect against development of PD itself. Presence of psychiatric illness, especially depression, may interfere with cognition and exacerbate memory loss. Reduction in the dose of dopaminergic agents and of other medications may be helpful in partially improving cognitive function in some cases. The balance between improvement of motor function and preservation of cognitive abilities must be weighed, and it is important for clinicians to discuss this trade-off with patients and their families. At this time, there is no US Food and Drug Administration-approved pharmacologic treatment for dementia in PD. However, medication used to treat Alzheimer's disease, such as acetylcholinesterase inhibitors, may slow progression of memory loss in some PD patients. Based on work from small double-blind studies, open-label trials, and case reports, cholinesterase inhibitors may be tried for treatment of dementia in PD, as long as the patient and caregivers understand that these agents are being used on an off-label basis. Surgical intervention, such as deep brain stimulation of the subthalamic nucleus or globus pallidus internus, although useful for treatment of motor symptoms in some PD patients, does not improve cognitive function in most cases and may actually worsen cognition in patients with pre-existing dementia. There is no specific exercise regimen or dietary guidelines for patients with PD who develop dementia. However, patients should be encouraged to lead a healthy lifestyle; this may improve overall well-being, which could impact positively on cognition function. Similarly, although assistive devices have not been developed for people with PD who have memory loss, any aid that increases mobility will probably improve mental and physical function. Clinicians should be mindful of the increased caregiver burden posed by PD patients who also have dementia. They should intervene appropriately to prevent caregiver distress and "burn out." Herbal and nutritional supplements have not been shown in clinical trials to be beneficial for treatment of any type of dementia, and thus are not recommended for PD patients with cognitive decline.
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PMID:Dementia in Parkinson's Disease. 1504 3

Parkinson syndrome occurs in the course of chemical intoxication, especially Mn, CS2, CO. It is rarely caused by chronic mercury intoxication. We present the case of 55 year old man who was exposed to metallic mercury vapor during 33 years of working in the chemical plant at the production of chlorine. On several occassions patient was removed from contact with Hg because of the symptoms of increased Hg absorption. At the age of 52 he developed hand tremor, balance and gait disturbance with bradykinesia, paresthesias of the upper extremities, neurobehavioral abnormalities, slight memory loss, and spatial disorientation. Psychoneurological examination revealed dementia, Parkinson's syndrome and ataxia of the lower limbs. Mercury excretion in the urine, which equaled 18.3 mu\g creatinine, confirmed exposure to Hg. MRI of the head revealed cortical and cerebellar atrophy. Electroneurography examination found features of subclinical peripheral sensory axonopathy of the upper limbs. Despite atypical clinical course (parkinsonismus) chronic mercury encephalopathy was diagnosed based on documented occupational exposure and diagnostic test results.
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PMID:[Parkinsonism in chronic occupational metallic mercury intoxication]. 1509 29

Alzheimer's disease (AD) is a progressive disease of aging primarily characterized at the behavioral level by symptoms of memory loss. The pathological hallmarks of AD are extracellular plaques and intracellular neurofibrillary tangles that are composed of filamentous polymers of beta-amyloid (Abeta) and tau, respectively. Aggregates of filaments are not unique to AD--fibrous polymers are the pathological signatures of many diseases of aging such as Huntington's disease and Parkinson's disease. Whether Abeta or tau filaments cause AD is still an open question, as a wide variety of proteins and pathways have been implicated in the initiation and advancement of the disease--processes such as apoptosis, oxidative stress, and protein degradation. That polymers are the prevalent species observed in aging disorders suggests that this morphology of aggregation represents a significant physiological role. As a consequence of an independent insult or aging itself, the filament shifts from a physiological role to one with pathological implications. The relative importance of Abeta filaments versus tau filaments has also been a focus of significant debate within the research community. Although genetic evidence indicates that Abeta filaments are an integral component in AD, only tau pathology has been found to correlate with symptom presentation in patients. Not only do tau filaments greatly contribute to the systematic loss of neurons and the pathological presentation of memory loss, but they may represent a physiological process whose regulation may be controlled.
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PMID:Can tau filaments be both physiologically beneficial and toxic? 1561 44

The cessation of ovarian estrogen production occurring around the time of menopause has the potential to influence central nervous system function, as well as a number of neurological disorders that affect women during midlife and old age, including memory loss and mild cognitive impairment, ischemic stroke, Parkinson's disease, and Alzheimer's disease. During midlife, there is observational evidence that episodic memory is not substantially affected by natural menopause or by use of estrogen-containing hormone therapy, but short-term clinical trial evidence suggests hormone therapy might benefit verbal memory after surgical menopause. Clinical trial data indicate that hormone therapy does not reduce, and may increase, stroke incidence. Parkinson's disease and Alzheimer's disease are the 2 most common neurodegenerative illnesses. Estrogen influences dopaminergic pathways within the central nervous system. However, available observational evidence is limited and inconclusive regarding any role of hormone therapy in influencing risk or symptoms of Parkinson's disease, a disorder of dopaminergic neurons. Finally, clinical trial data indicate that hormone therapy should not be initiated in the late postmenopause with the goal of improving memory, preventing cognitive decline, reducing dementia risk, or improving Alzheimer's disease symptoms. An important priority for clinical investigation is to determine whether hormone therapy used during the menopausal transition and early postmenopause has long-term effects on cognition or dementia risk. The critical window hypothesis as applied to Alzheimer's disease conjectures that effects of early hormone therapy might differ from those of hormone therapy initiated in the late postmenopause, but convincing evidence is yet to be obtained.
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PMID:Menopause and disorders of the central nervous system. 1630 63

Memory loss is an early symptom of Alzheimer's Disease (AD). The findings of Gong et al. (2006) now indicate that enhancing the activity of UCH-L1, a ubiquitin hydrolase, alleviates the synaptic dysfunction and memory loss associated with a mouse model of AD. This work also raises the question of what role UCH-L1 might play in other diseases involving protein aggregation, such as Parkinson's Disease.
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PMID:Improving synaptic function in a mouse model of AD. 1692 96

A 53-year-old man who had worked for 17 years manufacturing car batteries, with overt exposure to lead, developed a clinical picture initially characterized by signs of parkinsonism, followed by atypical signs such as loss of memory, reduction of eye movement, dysarthria, chorea-like dyskinesia and sexual impotence. The diagnosis of atypical parkinsonism was eventually changed to progressive supranuclear palsy-like parkinsonism. The patient was treated with various anti-Parkinson's disease drugs, including levodopa, with modest improvement. The symptoms deteriorated progressively, leading to permanent occupational disability with noticeable limitation of daily activities. Toxicological studies revealed abnormally high blood levels of lead. Discontinuation of lead exposure was followed first by clinical stabilization and then steady improvement. This case confirms recent reports that link exposure to lead and its compounds with degenerative diseases of the central nervous system, such as Parkinson's disease.
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PMID:Progressive supranuclear palsy-like parkinsonism resulting from occupational exposure to lead sulphate batteries. 1740 69

Information on changes in the central nervous system (CNS) cholinergic systems following exposure to manganese are considerably less extensive than that associated with other neurotransmitter systems. However, experimental and clinical evidence support the notion that cholinergic activity plays a key role in the pathophysiology of manganese-induced neurotoxicity. Manganese acts as a chemical stressor in cholinergic neurons in a region-specific manner causing breakdown of the cellular homeostatic mechanisms. In fact, a number of cholinergic synaptic mechanisms are putative targets for manganese activity: presynaptic choline uptake, quantal release of acetylcholine into the synaptic cleft, postsynaptic binding of acetylcholine to receptors and its synaptic degradation by acetylcholinesterase. Moreover, manganese significantly influences astrocytic choline transport systems and astrocytic acetylcholine-binding proteins. Thus, manganese exerts its effect on the highly dynamic reciprocal relationship between astrocytes and cholinergic neurons. Cholinergic afferents are crucial in the physiology of locomotion, cognition, emotion and behavioral response, and therefore, it is not surprising that the anatomical selectivity of most manganese-induced cholinergic effects is compatible with the clinical correlates of manganism, which involves impairment of emotional response, decline in higher cortical functions and movement disorder. Manganism, also referred to as Parkinson's-like disorder, is initially manifested by a neuropsychiatric syndrome (locura manganica), the most frequent symptoms and signs of which are compulsive behavior, emotional lability, visual hallucinations and flight of ideas, cognitive decline and memory loss. These signs and symptoms are followed by an extrapyramidal syndrome, which shares numerous clinical and pathophysiological characteristics with idiopathic Parkinson's disease (PD). This natural history of disease could be a clinical reflection of the preferential involvement of the cholinergic systems, initially in the septo-hippocampus and later in the basal ganglia. These observations highlight the importance of studying the role of the CNS cholinergic systems in manganese-mediated neurotoxicity.
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PMID:Modulation of cholinergic systems by manganese. 1792 Jan 28

Alzheimer's disease (AD) is a devastating neuro-degenerative disorder characterized by the progressive and irreversible loss of memory followed by complete dementia. Despite the disease's high prevalence and great economic and social burden, an explicative etiology or viable cure is not available. Great effort has been made to better understand the disease's pathogenesis, and to develop more effective therapeutic agents. However, success is greatly hampered by the presence of the blood-brain barrier that limits a large number of potential therapeutics from entering the brain. Nanoparticle-mediated drug delivery is one of the few valuable tools for overcoming this impediment and its application as a potential AD treatment shows promise. In this review, the current studies on nanoparticle delivery of chelation agents as possible therapeutics for AD are discussed because several metals are found excessive in the AD brain and may play a role in the disease development. Specifically, a novel approach involving transport of iron chelation agents into and out of the brain by nanoparticles is highlighted. This approach may provide a safer and more effective means of simultaneously reducing several toxic metals in the AD brain. It may also provide insights into the mechanisms of AD pathophysiology, and prove useful in treating other iron-associated neurodegenerative diseases such as Friedreich's ataxia, Parkinson's disease, Huntington's disease and Hallervorden-Spatz Syndrome. It is important to note that the use of nanoparticle-mediated transport to facilitate toxicant excretion from diseased sites in the body may advance nanoparticle technology, which is currently focused on targeted drug delivery for disease prevention and treatment. The application of nanoparticle-mediated drug transport in the treatment of AD is at its very early stages of development and, therefore, more studies are warranted.
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PMID:Metal chelators coupled with nanoparticles as potential therapeutic agents for Alzheimer's disease. 1993 78

Accumulation and deposition of beta amyloid (Abeta) play a critical role in the pathogenesis of Alzheimer's Disease (AD), and numerous approaches to control Abeta aggregation are being actively pursued. Brain Abeta levels are controlled by the action of several proteolytic enzymes such as neprilysin (NEP), insulin degrading enzyme (IDE) and plasmin. While up-regulation of these enzymes increased clearance of Abeta in transgenic mouse models of AD, these enzymes have other natural substrates and multiple cleavage sites in Abeta complicating their use for treating AD. Alternatively, immunotherapeutic approaches to clear Abeta are gaining interest. Active and passive immunization studies with Abeta can reduce plaque burden and memory loss, but clinical trials were stopped due to meningioencephalitis in some patients. Naturally occurring proteolytic antibodies have been shown to cleave Abeta, and their serum titers are increased in patients with AD reflecting a protective autoimmune response. These antibodies however cannot cross the blood brain barrier and depend entirely on peripheral clearance to clear Abeta. A potentially non-inflammatory approach to facilitate Abeta clearance and reduce toxicity is to promote hydrolysis of Abeta at its alpha-secretase site using affinity matured single chain antibody fragments (scFvs). Bispecific antibodies consisting of a proteolytic scFv and a targeting scFv can be engineered to selectively supplement and target extracellular alpha-secretase activity and to target toxic Abeta forms facilitating their degradation and clearance without generating an immune response. This strategy represents a suitable paradigm for treating other neurological diseases such as Parkinson's Disease, Lou Gehrig's Disease, and spongiform encephalopathies.
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PMID:Targeted hydrolysis of Beta-amyloid with engineered antibody fragment. 2008 8

Neurodegenerative diseases encompass a large group of neurological disorders. Clinical symptoms can include memory loss, cognitive impairment, loss of movement or loss of control of movement, and loss of sensation. Symptoms are typically adult onset (although severe cases can occur in adolescents) and are reflective of neuronal and glial cell loss in the central nervous system. Neurodegenerative diseases also are considered progressive, with increased severity of symptoms over time, also reflective of increased neuronal cell death. However, various neurodegenerative diseases differentially affect certain brain regions or neuronal or glial cell types. As an example, Alzheimer disease (AD) primarily affects the temporal lobe, whereas neuronal loss in Parkinson disease (PD) is largely (although not exclusively) confined to the nigrostriatal system. Neuronal loss is almost invariably accompanied by abnormal insoluble aggregates, either intra- or extracellular. Thus, neurodegenerative diseases are categorized by (a) the composite of clinical symptoms, (b) the brain regions or types of brain cells primarily affected, and (c) the types of protein aggregates found in the brain. Here we review the methods by which Drosophila melanogaster has been used to model aspects of polyglutamine diseases, Parkinson disease, and amyotrophic lateral sclerosis and key insights into that have been gained from these models; Alzheimer disease and the tauopathies are covered elsewhere in this special issue.
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PMID:Neurodegenerative models in Drosophila: polyglutamine disorders, Parkinson disease, and amyotrophic lateral sclerosis. 2056 20


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