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)

Parkinson's Disease (PD) is often associated with a subcortico-frontal syndrome (SCFS) that is mainly characterized by executive dysfunctions. The complete biochemistry of these dysfunctions remain misunderstood although many studies have suggested a role of the dopaminergic lesions. However, cholinergic lesions in this disease may also account for the SCFS occurrence. The present study has assessed the effects of an acute subclinical dose of scopolamine in normal controls and in PD patients who were devoid of cognitive deficit. Results indicates that PD patients but not normal controls developed a transient SCFS for the duration of the drug action. In contrast to other populations with cholinergic depletions - such as Alzheimer's disease - cholinergic blockage in PD exacerbates specifically the dysexecutive syndrome without inducing amnesia or sedation. Such a discrepancy between these two neuropsychological profiles are discussed in terms of the specificity of the underlying cholinergic lesions.
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PMID:Induction of a transient dysexecutive syndrome in Parkinson's disease using a~subclinical dose of scopolamine. 1156 19

The objective of the present investigation was to test the effects of benserazide/L-dopa treatment in a model of learning and memory deficits associated with early Parkinson's disease. Intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused a lesion in the substantia nigra, compact part and a specific loss of dopamine (DA) and its metabolites in the striatum of rats and a memory impairment in the two-way active avoidance task. The administration of benserazide/L-dopa (50 and 200 mg/kg) to the MPTP-lesioned rats restored the striatal level of DA, but did not reverse the MPTP-induced learning and memory impairment. As this treatment caused a large increase of DA levels in extrastriatal brain regions of the MPTP-lesioned animals, this study suggests that benserazide/L-dopa therapy was not effective in improving the observed learning impairment because this treatment appears to tilt the balance between DA levels in the striatum and in the extrastriatal regions, such as frontal cortex and limbic structures, resulting in a cognitive deficit.
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PMID:L-Dopa restores striatal dopamine level but fails to reverse MPTP-induced memory deficits in rats. 1180 61

Cognitive deficits affecting executive (frontal) functions have been widely described in Parkinson's disease (PD). However, dopa therapies are generally ineffective at reversing these deficits, except for tasks involving a sharing of attention such as working memory or simultaneous processing tasks. The aim of this study was to assess the relation between the nigrostriatal dopaminergic denervation in PD, as measured by SPECT with (123)Iodine-beta-CIT and the cognitive deficits, as measured by a simultaneous processing task, which had already been shown to be sensitive to dopa treatment. Ten patients with PD and ten control subjects were selected and matched for age, sex, and education. All subjects were assessed using computed visuo-auditory tasks which allow for the measurement of three cognitive processing conditions: 1) a Selective Processing Time; 2) a Competitive Processing Time; and 3) a Simultaneous Processing Time. Patients with PD were assessed both with (ON) and without (OFF) their usual dopaminergic treatment. The simultaneous processing condition but not the selective or the competitive conditions took significantly more time for patients with PD OFF than for either the control subjects or the patients with PD ON. In addition, when patients with PD were OFF, the simultaneous processing condition was correlated with the (123)Iodine-beta-CIT binding, but not when they were ON. These results suggest that nigrostriatal DA denervation may be involved in the specific impairment that patients with PD experience with simultaneous cognitive processing.
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PMID:Cognitive deficits and striatal dopaminergic denervation in Parkinson's disease: a single photon emission computed tomography study using 123iodine-beta-CIT in patients on and off levodopa. 1215 9

Cognitive deficits are often associated with Parkinson's disease (PD), although their prevalence in PD patients without dementia is still unknown. In order to describe the neuropsychological profile of PD patients without dementia, a sample of 103 PD patients was compared with a control group consisting of 38 healthy elderly subjects. Psychometric assessment consisted of the Mini Mental State Examination, the Dementia Rating Scale and a battery of neuropsychological tests. The Beck Depression Inventory was used to assess depression in PD patients. Dementia was diagnosed in 27 patients. Among non-demented subjects, 34 (45%) had no cognitive impairment and 42 (55%) had a mild cognitive impairment. Subjects with mild cognitive impairment were older, had a later onset of the disease, and more severe motor symptoms than cognitively intact subjects. Identification of mild cognitive impairment is important, since these symptoms are important for patient management and may also facilitate to determine prognosis.
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PMID:Neuropsychological profile of patients with Parkinson's disease without dementia. 1258 27

Cognitive decline, commonly first recognized as memory impairment, is a typical feature of Alzheimer's disease (AD). Neuropathological changes in the cerebral cortex and limbic system lead to deficits in learning, memory, language, and visuospatial skills. The precise nature of cognitive dysfunction reflects the distribution of pathological changes in AD. These will vary along the disease severity continuum and may also depend on where the disease sits in the spectrum of dementia. For example, AD-related disorders such as Lewy body dementia (LBD) and Parkinson's disease dementia (PDD) also show symptoms of cognitive decline and share several pathological features, including degeneration of cortical cholinergic and striatal dopaminergic neurons. In vascular dementia (VaD), there is often an unequal distribution of cognitive deficit, with severe impairment in some functions and relative sparing of others. Cholinesterase (ChE) inhibitors, which help restore acetylcholine levels in the brain, are licensed for the symptomatic treatment of AD and have shown additional benefit in related dementias. Physiological correlates of cholinergic function/dysfunction in the brain include regional cerebral blood flow, glucose metabolism, and cerebrospinal fluid levels of ChE enzymes. These variables represent valuable markers of the clinical efficacy of ChE inhibitors. However, direct assessment of cognitive improvement, stabilization or decline is usually considered the key efficacy parameter in clinical studies of ChE inhibitors in AD and related dementias. Large-scale, placebo-controlled clinical studies of ChE inhibitors have demonstrated efficacy in treating the cognitive impairments associated with AD. Randomized comparative studies of ChE inhibitors are now under way to directly compare symptomatic efficacy and effects on disease progression. Clinical trial data of the cognitive effects of ChE inhibitors in AD, LBD, PDD, and VaD are discussed in detail in this article. The benefits of long-term treatment on symptomatic improvement in cognition and further potential disease-modifying effects are highlighted.
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PMID:The ABC of Alzheimer's disease: cognitive changes and their management in Alzheimer's disease and related dementias. 1263 80

Measurement of local cerebral glucose metabolism (lCMRGlc) by positron emission tomography (PET) and 18F-2-fluoro-2-deoxy-D-glucose (FDG) has become a standard technique during the past 20 years and is now available at many university hospitals in all highly developed countries. Many studies have documented a close relation between lCMRGlc and localized cognitive functions, such as language and visuoconstructive abilities. Alzheimer's disease (AD) is characterized by regional impairment of cerebral glucose metabolism in neocortical association areas (posterior cingulate, temporoparietal and frontal multimodal association cortex), whereas primary visual and sensorimotor cortex, basal ganglia, and cerebellum are relatively well preserved. In a multicenter study comprising 10 PET centers (Network for Efficiency and Standardisation of Dementia Diagnosis, NEST-DD) that employed an automated voxel-based analysis of FDG PET images, the distinction between controls and AD patients was 93% sensitive and 93% specific, and even in very mild dementia (at MMSE 24 or higher) sensitivity was still 84% at 93% specificity. Significantly abnormal metabolism in mild cognitive deficit (MCI) indicates a high risk to develop dementia within the next two years. Reduced neocortical glucose metabolism can probably be detected with FDG PET in AD on average one year before onset of subjective cognitive impairment. In addition to glucose metabolism, specific tracers for dopamine synthesis (18F-F-DOPA) and for (11C-MP4A) are of interest for differentiation among dementia subtypes. Cortical acetylcholine esterase activity (AChE) activity is significantly lower in patients with AD or with dementia with Lewy bodies (DLB) than in age-matched normal controls. In LBD there is also impairment of dopamine synthesis, similar to Parkinson disease.
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PMID:PET studies in dementia. 1279 Mar 55

Neuropsychiatric, perceptual and cognitive deficits are increasingly recognized as non-motor manifestations of Parkinson's Disease (PD).The premorbid personality profile of PD patients is characterized by a number of traits which figure prominently after the disease becomes manifest. In particular, less novelty seeking is one premorbid trait providing an understanding of later cognitive deficits. Anxiety and depression have been shown to precede in some patients motor manifestations and cannot be attributed to anti-parkinsonian therapy. Some neuropsychiatric manifestations and in particular hallucinosis are linked to select perceptual and cognitive changes. Cognitive deficits are common in PD, in particular in younger onset patients. Current animal studies link genetic differences in the dopamine transporter and dopamine catabolic enzyme system to select cognitive impairments attributed to frontal lobe dysfunction.Visuo-cognitive impairment is prevalent in PD. Retinal dopaminergic deficiency has been shown in patients and in the animal model of PD. Visuo-spatial deficits, however, are not simply passive reflections of retinal deficiency. In addition to vision, saccadic eye movements are affected in PD whether they contribute to visuo-spatial dysfunction is unknown. However, recent functional Magnetic Resonance Imaging (fMRI) and electroencephalogram (EEG) studies show an essential role of the occipital cortex in saccadic eye movements and positron emission tomography (PET) studies show occipital hypometabolism in PD. Visual and eye movement studies suggest that certain neuropsychiatric and cognitive deficits in PD are linked to the visual system. Synchrony of signals are essential for the co-operation of distributed neuronal network engaged in sensory-motor coordination. Local, dopaminergic neuronal groups in the retina, basal ganglia and frontal cortical memory system are affected in PD. These connections may not primarily rely on dopamine as a neurotransmitter. It is suggested that to understand visuocognitive changes we should consider pathology affecting neuronal connections, necessary for binding parallel distributed networks.
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PMID:Neuropsychological and perceptual defects in Parkinson's disease. 1291 72

The Lewy body, an eosinophilic inclusion around 10 microns in diameter, is localised in the neuronal perikaryon. Its dense core is surrounded by a clear halo, which is lacking in the so-called "cortical Lewy bodies". Numerous proteins have been identified in Lewy bodies, among which the three neurofilament isoforms, ubiquitin and proteasome subunits. More recently, alpha-synuclein--a pre-synaptic protein--has been found to be the essential constituent of the Lewy body. Alpha-synuclein antibody has greatly increased the sensitivity of the neuropathological examination: it has emphasized the frequency of "Lewy neurites" (accumulation of alpha--synuclein in neuronal processes) and has shown the importance of extra-nigral pathology. Lewy bodies and neurites are indeed to be found in many areas of the central and peripheral nervous system: stellate ganglia, cardiac and enteric plexus, pigmented nuclei of the brainstem, basal nucleus of Meynert, amygdala, limbic nuclei of the thalamus, parahippocampal and cingulate gyri, insula and isocortex. Lewy body diseases include at least three clinical syndromes: 1) idiopathic Parkinson disease in which the brainstem bears the brunt of the pathology 2) Parkinson disease dementia in which Lewy lesions are found in the brainstem and are also abundant in the isocortex. A large number of senile plaques is frequently associated. 3) In dementia with Lewy bodies, the same lesions are observed but the cognitive deficit occurs first or shortly (less than one year) after the motor symptoms.
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PMID:[Lewy bodies, a misleading marker for Parkinson's disease?]. 1455 41

Cognitive deficits in Parkinson's disease (PD) include disturbances in working memory. We examined sequential visuo-spatial memory span by means of an adaptation of the Corsi Block-Tapping Task in groups of medicated (n=14) and non-medicated (n=15) patients with early stage PD, and in control subjects (n=22). A deficit in memory span was found in medicated patients with early stage PD relative to controls. There were no differences between non-medicated patients relative to either controls or medicated patients. A decrease in sequential visuo-spatial memory span appears to be a relatively early feature of PD and most likely reflects executive rather than mnemonic dysfunction.
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PMID:Deficits on Corsi's block-tapping task in early stage Parkinson's disease. 1464 1

Degeneration of nigrostriatal dopamine neurons and cholinergic cortical neurones are the main pathological features of Parkinson's disease (PD) and for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB), respectively. Many PD and DLB subjects have dementia and depression resulting from possible degeneration of cholinergic and noradrenergic and serotonergic neurons. On the other hand, AD patients may also develop extrapyramidal features as well as depression. In both PD and AD there is, respectively, accumulation of iron within the melanin containing dopamine neurons of pars compacta and with in the plaques and tangle. It has been suggested that iron accumulation may contribute to the oxidative stress induced apoptosis reported in both diseases. This may result from increased glia hydrogen peroxide producing monoamine oxidase (MAO) activity that can generate of reactive hydroxyl radical formed from interaction of iron and hydrogen peroxide. We have therefore prepared a series of novel bifunctional drugs from the neuroprotective-antiapoptotic antiparkinson monoamine oxidase B inhibitor, rasagiline, by introducing a carbamate cholinesterase (ChE) inhibitory moiety into it. Ladostigil (TV-3326, N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), has both ChE and MAO-AB inhibitory activity, as potential treatment of AD and DLB or PD subjects with dementia Being a brain selective MAO-AB inhibitor it has limited potentiation of the pressor response to oral tyramine and exhibits antidepressant activity similar to classical non-selective MAO inhibitor antidepressants by increasing brain serotonin and noradrenaline. Ladostigil inhibits brain acetyl and butyrylcholinesterase in rats and antagonizes scopolamine-induced inhibition of spatial learning. Ladostigil like MAO-B inhibitor it prevents MPTP Parkinsonism in mice model and retains the in vitro and in vivo neuroprotective activity of rasagiline. Ladostigil, rasagiline and other propargylamines have been demonstrated to have neuroprotective activity in several in vitro and in vivo models, which have been shown be associated with propargylamines moiety, since propargylamines itself possess these properties. The mechanism of neuroprotective activity has been attributed to the ability of propargylamines-inducing the antiapoptotic family proteins Bcl-2 and Bcl-xl, while decreasing Bad and Bax and preventing opening of mitochondrial permeability transition pore. Iron accumulates in brain regions associated with neurodegenerative diseases of PD, AD, amyotrophic lateral sclerosis and Huntington disease. It is thought to be involved in Fenton chemistry oxidative stress observed in these diseases. The neuroprotective activity of propargylamines led us to develop several novel bifunctional iron chelator from our prototype brain permeable iron chelators, VK-28, possessing propargylamine moiety (HLA-20, M30 and M30A) to iron out iron from the brain. These compounds have been shown to have iron chelating and monoamine oxidase A and B selective brain inhibitory and neuroprotective-antiapoptotic actions.
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PMID:Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases. 1562 Dec 13


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