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)

Motor symptoms in Parkinson's disease (PD) are associated with complex changes of firing properties in basal ganglia output neurons (BGON). The abnormalities are generally attributed to altered synaptic input and potential post-synaptic mechanisms are currently unknown. Our cell-type selective transcriptome analyses of BGON in the rat 6-hydroxydopamine (6-OHDA) model of PD identified the ion channel HCN3 as a likely contributor to altered neuronal excitability. Quantitative PCR experiments confirmed the HCN3 upregulation in the rat and mouse 6-OHDA models and also demonstrated selectivity of the effect for HCN3. In accordance with the mRNA expression data, in vitro whole cell patch-clamp recordings in BGON showed increased HCN3 current amplitudes and increased rebound excitability in BGON of 6-OHDA treated rats. These data establish HCN3 up-regulation as a novel candidate mechanism that might contribute to the in vivo changes of electrical activity in basal ganglia output neurons of the parkinsonian brain.
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PMID:Dopamine depletion induced up-regulation of HCN3 enhances rebound excitability of basal ganglia output neurons. 1932 57

More therapeutic options have become available for Parkinson's disease (PD) in recent years, leading to significant improvements in motor control both at early and advanced disease stages. More importantly, the need to expand disease management beyond motor symptom control has been recently highlighted and contribution of non-motor features to quality of life is now relevant. Dopamine agonists represent a valid therapeutic option in PD and their effect on non-motor domains like mood or cognition is now acknowledged as a key factor in fully addressing patients' needs. Pramipexole is a well established dopamine agonist that is currently being investigated for its potential disease-modifying effect and action on mood in PD. In this review we will examine factors contributing to treatment decision-making and discuss how a proper balance between motor and non-motor features should be aimed for in approaching PD therapy.
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PMID:Dopamine agonist-based strategies in the treatment of Parkinson's disease. 1938 65

Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility in PD include early satiety and weight loss from delayed gastric emptying and constipation from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the parkinsonian neurotoxin and mitochondrial complex I inhibitor rotenone causes delayed gastric emptying and enteric neuronal dysfunction when administered chronically to rats in the absence of major motor dysfunction or CNS pathology. When examined 22-28 days after initiation of rotenone infusion by osmotic minipump (3 mg/kg/day), 45% of rotenone-treated rats had a profound delay in gastric emptying. Electrophysiological recording of neurally-mediated muscle contraction in isolated colon from rotenone-treated animals confirmed an enteric inhibitory defect associated with rotenone treatment. Rotenone also induced a transient decrease in stool frequency that was associated with weight loss and decreased food and water intake. Pathologically, no alterations in enteric neuron numbers or morphology were apparent in rotenone-treated animals. These results suggest that enteric inhibitory neurons may be particularly vulnerable to the effects of mitochondrial inhibition by parkinsonian neurotoxins and provide evidence that parkinsonian gastrointestinal abnormalities can be modeled in rodents.
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PMID:Delayed gastric emptying and enteric nervous system dysfunction in the rotenone model of Parkinson's disease. 1940 96

Motor symptoms of Parkinson's disease (PD) do not appear until the majority of dopaminergic cells in the substantia nigra pars compacta are lost, suggesting significant redundancy or compensation in the motor systems affected by PD. Using functional magnetic resonance imaging, we examined whether compensation in PD is manifested by changes in amplitude and/or spatial extent of activity within normal networks (active motor reserve) and/or newly recruited regions [novel area recruitment (NAR)]. Ten PD subjects off and on medication and 10 age-matched controls performed a visually guided sinusoidal force task at 0.25, 0.5 and 0.75 Hz. Regression was used to determine the combination of regions where activation amplitude scaled linearly with movement speed in controls. We then determined the activation of PD subjects in this network, as well as the corresponding PD network. To measure the spatial variance of activation, we used an invariant spatial feature approach. Control subjects monotonically increased activity within striato-thalamo-cortical and cerebello-thalamo-cortical regions with increasing movement speed. In PD subjects, the activity of this network at low speeds was similar to that in controls at higher speeds. Additionally, PD subjects off medication demonstrated NARs of the bilateral cerebellum and primary motor cortex, which were incompletely normalized by levodopa. Our results suggest that PD subjects tap into motor reserve, increase the spatial extent of activation and demonstrate NAR to maintain near-normal motor output.
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PMID:Motor reserve and novel area recruitment: amplitude and spatial characteristics of compensation in Parkinson's disease. 1949 21

Processing irrelevant visual information sometimes activates incorrect response impulses. The engagement of cognitive control mechanisms to suppress these impulses and make proactive adjustments to reduce the future impact of incorrect impulses may rely on the integrity of frontal-basal ganglia circuitry. Using a Simon task, we investigated the effects of basal ganglia dysfunction produced by Parkinson's disease (PD) on both on-line (within-trial) and proactive (between-trial) control efforts to reduce interference produced by the activation of an incorrect response. As a novel feature, we applied distributional analyses, guided by the activation-suppression model, to differentiate the strength of incorrect response activation and the proficiency of suppression engaged to counter this activation. For situations requiring on-line control, PD (n = 52) and healthy control (n = 30) groups showed similar mean interference effects (i.e., Simon effects) on reaction time (RT) and accuracy. Distributional analyses showed that although the strength of incorrect response impulses was similar between the groups PD patients were less proficient at suppressing these impulses. Both groups demonstrated equivalent and effective proactive control of response interference on mean RT and accuracy rates. However, PD patients were less effective at reducing the strength of incorrect response activation proactively. Among PD patients, motor symptom severity was associated with difficulties in on-line, but not in proactive, control of response impulses. These results suggest that basal ganglia dysfunction produced by PD has selective effects on cognitive control mechanisms engaged to resolve response conflict, with primary deficits in the on-line suppression of incorrect responses occurring in the context of a relatively spared ability to adjust control proactively to minimize future conflict.
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PMID:The effect of Parkinson's disease on the dynamics of on-line and proactive cognitive control during action selection. 1970 65

Levodopa is the cornerstone treatment for Parkinson's disease, but the short half-life of levodopa limits its usefulness in late stages of the disease. Duodenal levodopa infusion (DLI) allows more stable plasma levels and better motor symptom control. To explore the costs and health benefits of replacing conventional oral polypharmacy with DLI in patients with advanced Parkinson's disease, from a Swedish healthcare payer perspective. Based on a clinical, randomized, crossover study with 24 patients (DIREQT), a decision analytic model predicted 2-year drug costs and QALYs for conventional oral therapy and for DLI. Health-related quality of life (HR-QOL) was recorded using a 15-dimensional (15D) utility instrument at baseline and during the two 3-week trial periods, and then at eight follow-up visits during the subsequent 6 months. Use of medication was based on data from DIREQT and previous studies. Unit costs were based on market prices (drugs) and customary charges in Sweden. All costs were expressed in Swedish kronor (SEK), year 2004 values euro 1.00 approximately SEK9.17, $US1.00 = SEK7.47). Future costs and outcomes were discounted at 3%. One-way and probabilistic sensitivity analyses were conducted. The mean utility scores were 0.77 for DLI and 0.72 for conventional therapy (p = 0.02). A considerable variation in the scores was observed during the study. The expected per-patient 2-year cost of DLI was SEK562 000 while it was SEK172 000 for conventional therapy. The mean number of QALYs was 1.48 and 1.42, respectively, representing an incremental cost of SEK6.1 million per QALY for DLI (all values discounted at 3%). Using other assumptions in sensitivity analyses, the cost per QALY could be as low as SEK456 000. This analysis can be considered exploratory only; it is based on very limited data. Nevertheless, our findings suggest that DLI results in a significant improvement in HR-QOL. However, the cost per QALY is likely to be higher than customary cost-effectiveness thresholds. Whether these benefits justify the additional costs depends on how the health benefits are measured and how these benefits are valued by society.
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PMID:Short-term cost and health consequences of duodenal levodopa infusion in advanced Parkinson's disease in Sweden: an exploratory study. 1979 71

PD occurring in married couples, "conjugal PD" represents a unique opportunity to study environmental risk factors for PD due to the shared environment. This retrospective study of non-related married individuals who both presented to the Washington University Movement Disorders Center between 1994 and 2005 investigated the clinical presentation, therapy response, and disease course in conjugal PD subjects. In addition, an occupational, residential, and environmental survey was administered to elucidate potential shared environmental risk factors. Eighteen married subjects had a clinical picture suggestive of idiopathic Parkinson disease. Average age of motor symptom onset was 66.1 (+/-6.22) years in women, 63.4 (+/-7.87) years in men. Subjects cohabitated an average of 39.9 years prior to motor symptom onset in the first affected spouse and an average of nine years elapsed prior to symptom onset in their partner. Disease course in conjugal pairs varied substantially. Seventeen out of eighteen subjects reported at least one environmental exposure of interest. Concordant exposures were residential, non-occupational pesticide and heavy metal exposure, each reported by 77.8% (7/9) of couples. Multiple exposures were reported by 88.9% (16/18) of subjects, most often residential agricultural chemical and heavy metal in combination. This case series of conjugal PD suggests that combined residential exposures may be important in the pathogenesis of idiopathic PD. Larger conjugal PD studies may permit stratification of concordant environmental exposures to determine dose responsiveness and relative contributions to PD risk.
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PMID:Conjugal Parkinsonism and Parkinson disease: a case series with environmental risk factor analysis. 2006 Nov 76

PD is a neurodegenerative disorder triggered by genetic and/or environmental factors and the pathological processes begin many years before motor symptom manifestation. Several drugs are available to treat PD, but there are still many aspects of the disease that have not been well addressed. These include nonmotor symptoms, disease progression, and preventing levodopa-induced motor complications. Besides the concept of continuous dopaminergic stimulation, the benefit of which has not been proved in clinical settings (see the STRIDE-PD trial), the nondopaminergic drugs offer promising alternatives to dopaminergic medication. However, modification and further development of dopaminergic molecules may provide significant symptomatic improvement and improved quality of life. In this review, we summarized new treatments that are in the pipeline, with patients being recruited for clinical trials. Among the compounds being studied are well-known ones (e.g., folic acid or methylphenidate), which have been used in other diseases, and newly developed drugs with known mode of action (e.g., the dopamine agonist aplindore) or compounds with completely new mechanisms, which have not yet been used in clinical settings (e.g., levetiracetam or Neu 120). A major breakthrough in treating Parkinson's disease cannot be expected with molecules from the first two cases, whereas significant clinical benefits can be predicted with the drugs in the last group. However, without these large-scale, well-designed, multicenter trials, the promising preclinical results cannot be directly adopted in patient care. Hopefully, some of these trials will end soon with positive results, and certain drugs will become available with which to treat PD patients, although still many aspects (e.g., the most problematic one, the question of neuroprotection) still need to be addressed.
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PMID:Novel therapeutic strategies in Parkinson's disease. 1983 98

Altered sleep is a common non motor symptom in Parkinson's disease. Sleep dysfunction has been reported to occur in 60-90% of all PD patients, having a detrimental impact on quality of life and increasing disability. alpha-Synuclein deposits in the lower brainstem affecting autonomic and sleep regions have been identified in the pathophysiology. The resultant non motor symptoms such as REM sleep behaviour disorder (RBD) can precede the motor symptoms by years. RBD is violent, enacted dreams that expose the patient or their sleeping partner to night-time injuries. Excessive daytime sleepiness, sometimes with a narcolepsy-like phenotype, is a common occurrence in PD, owing to lesions in the arousal systems of the brain. Restless legs syndrome and sleep disordered breathing can all affect daytime alertness of PD patients. Autonomic deregulation can also negatively affect sleep patterns, by adding to night-time wakening and disrupting sleep.
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PMID:Sleep dysfunction and role of dysautonomia in Parkinson's disease. 2008 18

Non-ergot dopamine receptor agonists, such as ropinirole, pramipexole, rotigotine and apomorphine, may alleviate some non-motor symptoms in Parkinson's disease (PD) while others may be precipitated. In this review, we discuss how dopamine receptor agonists can both ameliorate and aggravate the sleep problems in PD, a key non-motor symptom of this disease.
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PMID:Dopamine receptor agonists and sleep disturbances in Parkinson's disease. 2012 46


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