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)

Current therapies for Parkinson's disease (PD) are limited in their ability to control PD symptomatology, are associated with motor and psychiatric side effects, and do not prevent disease progression. Considerable scientific and media interest has focused on the potential value of gene and stem cell therapies to overcome these problems and to enhance the quality of life for PD patients. Gene therapies utilize a viral vector to deliver a protein of interest to specific brain region. Clinical trials of gene therapy are currently underway using adeno-associated virus to deliver AADC to the striatum, the trophic factor nurturin to the striatum, and GAD to the STN. To date, no serious adverse effects have been noted, but only a small number of patients have been studied. Stem cells are pluripotential cells that offer the potential of generating unlimited numbers of optimized dopamine cells for transplantation. Stem cells can be grown and expanded in tissue culture and then induced to differentiate into dopamine neuronal phenotypes. Transplantation of these cells into the striatum is associated with behavioral improvement in 6-OHDA rodents and MPTP monkeys. Still, only small numbers of transplanted dopaminergic cells survive, and benefits are modest. Clinical trials in PD have not yet been performed. There is considerable enthusiasm for the potential of these procedures, but there remains much to learn in the laboratory and neither has been established to be effective as a treatment for PD. Long term safety and efficacy trials have not been performed in PD patients and the potential of unanticipated side effects must be addressed. Further, neither treatment is expected to improve the non-dopaminergic features of PD.
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PMID:Gene transfer of trophic factors and stem cell grafting as treatments for Parkinson's disease. 1671 56

To determine whether the degree to which a patient with Parkinson's disease expects therapeutic benefit from subthalamic nucleus-deep brain stimulation (STN-DBS) influences the magnitude of his or her improved motor response, 10 patients with idiopathic Parkinson's and bilateral STN-DBS were tested after a 12-hour period off medication and stimulation. Four consecutive UPDRS III scores were performed in the following conditions: (a) stimulation OFF, patient aware; (b) stimulation OFF, patient blind; (c) stimulation ON, patient aware; and (d) stimulation ON, patient blind. Statistical significance (P = 0.0001) was observed when comparing main effect ON versus OFF (mean ON: 32.55; mean OFF: 49.15). When the stimulation was OFF, patients aware of this condition had higher UPDRS motor scores than when they were blinded (mean: 50.7 vs. 47.6). With the stimulation ON, UPDRS motor scores were lower when the patients were aware of the stimulation compared with when they were blinded (mean: 30.6 vs. 34.5). The interaction between these levels was significant (P = 0.049). This variation was important for bradykinesia and was not significant for tremor and rigidity. The authors conclude that the information about the condition of the stimulation enhanced the final clinical effect in opposite directions. The results presented support the role of expectation and placebo effects in STN-DBS in Parkinson's disease patients.
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PMID:Expectation and the placebo effect in Parkinson's disease patients with subthalamic nucleus deep brain stimulation. 1672 50

Sequence learning, a cognitive task linked to cortico-striatal function, is impaired in Parkinson's disease (PD). We chose this task as a behavioral paradigm to study the functional architecture of PD in treated and untreated conditions. In our studies, participants were scanned with H(2)(15)O while performing a kinematically controlled motor sequence learning task and a matching motor baseline task. Experiments revealed that a specific sequence learning network predicts learning in normal subjects, and in independent cohorts of early and advanced PD patients. The analysis of the relationship of network activity to learning performance revealed diverging influences of dopaminergic therapy and deep brain stimulation (DBS). DBS of the internal GP and of STN increased network activity and task performance, while levodopa decreased both measures. In separate studies, we investigated the role of dopaminergic modulation on brain activation during sequence learning. In healthy subjects dopamine transporter (DAT) binding correlated with learning-related brain activation in prefrontal, premotor and cingulate cortices, and in the thalamus. By contrast, in PD most of these regional relationships were lost. Only ventral and dorsolateral prefrontal cortex activation correlated with caudate dopaminergic input. In a final set of studies, we found a significant decline in learning performance in early stage PD patients followed over the course of 2 years. Longitudinal declines in learning-related activation were found in parietal areas, while concomitant increases were localized to the left hippocampus. These observations support hypotheses on disease-stage and task-specific effects within the different cortico-striato-pallido-thalamocortical loops and the mesocortical system in PD.
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PMID:Functional imaging of sequence learning in Parkinson's disease. 1675 82

It has been proposed that deep brain stimulation (DBS) of the subthalamic nucleus (STN DBS) and dopaminergic therapy ameliorate the symptoms of Parkinson's disease through similar functional mechanisms. We examined this notion using PET to compare the metabolic effects of these treatment approaches. Nine Parkinson's disease patients (age 61.7 +/- 11.1 years) were scanned ON and OFF STN stimulation and nine others (age 60.0 +/- 9.3 years) were scanned ON and OFF an individual titrated intravenous levodopa infusion. The two treatment groups were matched for baseline disease severity as well as clinical response to therapy. Similarities and differences in the effects of treatment on regional metabolism were assessed using statistical parametric mapping (SPM). In addition, we used network analysis to assess the effect of therapy on the expression of an abnormal Parkinson's disease-related spatial covariance pattern (PDRP). We found that both STN DBS and levodopa therapy were associated with significant (P < 0.001) metabolic reductions in the putamen/globus pallidus, sensorimotor cortex and cerebellar vermis, as well as increases in the precuneus (BA 7). The metabolic effects of the two interventions differed in the STN and medial prefrontal cortex, with relative increases with stimulation in the former structure and decreases in the latter. Network quantification disclosed reductions in PDRP activity with both interventions, which correlated with clinical improvement (P < 0.05). The degree of network modulation by therapy did not differ significantly for the two treatment approaches (P > 0.6). These findings support the results of previous imaging studies indicating that effective symptomatic therapies for Parkinson's disease involve a common mechanism. The modulation of pathological brain networks is a critical feature of the treatment response in parkinsonism.
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PMID:Network modulation in the treatment of Parkinson's disease. 1684 13

The goal of this study is to examine the association of depression with intelligence and education in patients with Parkinson's disease treated with bilateral subthalamic nucleus stimulation (STN-DBS). The literature has been contradictory concerning depression in Parkinson's disease patients. Some studies have shown less depression in Parkinson's disease patients with more education not treated with STN-DBS. Other recently published studies indicate that STN-DBS improves the depression associated with Parkinson's disease. No studies have examined the correlation of these factors with depression in Parkinson's disease patients treated with STN-DBS. We administered the Beck Depression Inventory (BDI) pre- and postoperatively to 21 Parkinson's disease patients (seven women, 14 men, ages 49-75) who underwent STN-DBS. The postoperative scores of the lower 50th percentile (n=8) of the Verbal Comprehensive Index of the Wechsler Adult Intelligence Scale (WAIS-III) decreased significantly (P=0.036), while the upper 50th percentile (n=13) remained nearly constant (P=0.802). Furthermore, as the education increased from highschool to graduate level, patients demonstrated less improvement in depressive symptoms postoperatively. These findings suggest that Parkinson's disease patients with lower intelligence test scores and less education benefit more with regards to depressive symptomatology after STN-DBS than patients with higher scores and education.
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PMID:Depression and intelligence in patients with Parkinson's disease and deep-brain stimulation. 1689 82

We examined the direct effect of deep brain stimulation of the subthalamic nucleus (STN-DBS) on levodopa-induced peak-dose dyskinesia in 45 patients with Parkinson's disease (PD) without reducing the levodopa dosage during the early period after surgery. In 8 patients (18%), the dyskinesia was quickly attenuated by bipolar stimulation in an experimental trial (5 min) with the contacts placed within the area above the STN. In contrast, bipolar stimulation using contacts placed within the STN itself tended to provoke or exacerbate the dyskinesia, indicating that dyskinesia could be inhibited by stimulation of the areas above the STN rather than the STN itself. In an attempt to control the cardinal symptoms of PD and dyskinesia at the same time, we employed bipolar stimulation with a longer interpolar distance as a therapeutic procedure (2 weeks), using contacts within the STN as a cathode and contacts within the area above the STN as an anode. Bilateral STN-DBS significantly attenuated the dyskinesia as evaluated by the dyskinesia severity rating scale (p < 0.05). In 24 patients (53%), almost complete control of the dyskinesia was observed. The contacts used as an anode in these patients were located more dorsally compared to those of the remaining patients, suggesting again that the dyskinesia was inhibited by stimulation of the areas above the STN rather than the STN itself. In the area above the STN, pallidothalamic, pallidosubthalamic and subthalamopallidal fibers are densely distributed. It appears that stimulation of these fibers may cause effects similar to thalamic or pallidal DBS and therefore inhibit peak-dose dyskinesia. Bipolar STN-DBS with contacts placed within the area above the STN as an anode appears to represent a useful option for controlling both the cardinal symptoms of PD and peak-dose dyskinesia at the same time.
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PMID:Direct effect of subthalamic nucleus stimulation on levodopa-induced peak-dose dyskinesia in patients with Parkinson's disease. 1690 80

In patients with Parkinson's disease, deep brain stimulation of the subthalamic nucleus is known to impair their ability to correctly identify facial expressions of negative emotions. This difficulty exists only when the stimulator is active. The reason for the impairment is unknown. To test the hypothesis that the stimulation itself is responsible, we used positron emission tomography to compare functional activations of brain regions in nine patients with Parkinson's disease treated with surgically implanted electrodes into both subthalamic nuclei, and 22 healthy volunteers. Both groups viewed images with neutral or emotional content from Aarhus University's standard Empathy Picture System () with 360 images of people in pleasant, unpleasant or neutral real-life situations, presenting either the situations or close-ups of the facial expressions of the people involved. Both groups, the patients with stimulation OFF and the healthy volunteers, had raised regional blood flow rates (rCBF) in the right fusiform gyrus when they viewed emotionally expressive faces compared to neutral faces. With stimulation turned on, this response was significantly inhibited in the patients because of a raised rCBF at baseline during the neutral faces. Stimulation of the STN did not alter fusiform reaction to emotionally pregnant scenes; nor did healthy volunteers and patients react differently to these stimuli regardless of stimulation status. Also, STN stimulation raised the emotional activation of the anterior cingulate and lowered the activity of the putamen. The findings suggest that the stimulation of the subthalamic nucleus interferes with the integration of specific neocortical networks involved in the recognition of facial expressions.
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PMID:Stimulation of subthalamic nucleus inhibits emotional activation of fusiform gyrus. 1695 96

To investigate the bilateral effects of unilateral subthalamic nucleus deep brain stimulation (STN-DBS), we prospectively studied 9 consecutive advanced Parkinson's disease (PD) patients (2 men and 7 women) who underwent unilateral STN-DBS. Patients were evaluated preoperatively and at 3 and 6 months postoperatively with and without dopaminergic medications ('on' and 'off' medication, respectively). Postoperatively, patients were assessed with and without stimulation. We found that, when compared with baseline, the 'off' medication scores of the Unified Parkinson's Disease Rating Scale motor part (UPDRS III) and activities of daily living (UPDRS II) were improved by 37% (p = 0.028) and 50% (p = 0.046) at 6 months after surgery, respectively. Stimulation while 'off' medication improved the total UPDRS score by 42% (p = 0.028) at 6 months. At 6 months after surgery, the subscore of UPDRS III of body parts contralateral to the DBS implantation had improved by 48% (p = 0.028), and the ipsilateral subscore of UPDRS III and the axial subscore of UPDRS III had improved by 20% (p = 0.027) and 39% (p = 0.028), respectively. Daily dosage of levodopa was reduced by 15% at 6 months. No patient exhibited permanent side effects. These findings indicate that unilateral STN-DBS may be a reasonable surgical procedure for selected PD patients who have markedly asymmetric parkinsonism.
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PMID:Bilateral effects of unilateral subthalamic nucleus deep brain stimulation in advanced Parkinson's disease. 1696 Apr 54

The neurobiological mechanisms by which high-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates the motor symptoms of Parkinson's disease (PD) remain unclear. In this study, we analyzed the effects of STN-HFS on motor behavior in intact or hemiparkinsonian rats (6-hydroxydopamine lesion of the substantia nigra pars compacta) and investigated the correlation between these effects and extracellular glutamate (Glu) and GABA levels, assessed by intracerebral microdialysis in the substantia nigra pars reticulata (SNr). STN-HFS at an intensity corresponding to the threshold inducing contralateral forelimb dyskinesia, increased Glu levels in the SNr of both intact and hemiparkinsonian rats. In contrast, STN-HFS at half this intensity did not affect Glu levels in the SNr in intact or hemiparkinsonian rats but increased GABA levels in hemiparkinsonian rats only. STN-HFS-induced forelimb dyskinesia was blocked by microinjection of the Glu receptor antagonist kynurenate into the SNr and facilitated by microinjection of a mixture of the Glu receptor agonists AMPA and NMDA into the SNr. These new neurochemical data suggest that STN-HFS-induced forelimb dyskinesia is mediated by glutamate, probably via the direct activation of STN axons, shedding light on the mechanisms of STN-HFS in PD.
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PMID:Subthalamic stimulation-induced forelimb dyskinesias are linked to an increase in glutamate levels in the substantia nigra pars reticulata. 1731 40

Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective therapy for off-period motor symptoms and dyskinesias in advanced Parkinson's disease. Clinical studies have shown that STN-DBS also ameliorates urinary bladder function in Parkinson's disease patients by delaying the first desire to void and increasing bladder capacity. This study aimed at investigating the effect of STN-DBS on the neural mechanisms underlying cerebral bladder control. Using PET to measure changes in regional cerebral blood flow (rCBF), 11 patients with bilateral STN-DBS were studied during urodynamic bladder filling in STN-DBS ON and OFF condition. A filled bladder led to a significant increase of rCBF in the anterior cingulate cortex, which was further enhanced during STN-DBS OFF. A significant interaction between bladder state and STN-DBS was observed in lateral frontal cortex with increased rCBF when the bladder was filled during STN-DBS OFF. The data suggest that STN-DBS ameliorates bladder dysfunction and that this modulation may result from facilitated processing of afferent bladder information.
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PMID:Subthalamic stimulation modulates cortical control of urinary bladder in Parkinson's disease. 1707 5


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