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)

In hepatic encephalopathy, a progressive and diffuse impairment in brain function is associated with gradual alterations that can be detected by magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS). In some patients, a variety of movement disorders suggestive of extrapyramidal impairment points toward basal ganglia (BG) alterations. Accordingly, (i) hyperintensities at MRI predominant in the pallidum, an important region of BG involved in the motor control, (ii) redistribution of cerebral blood flow from cortical areas to BG structures observed using positron emission tomography studies, and (iii) the preferential pallidal location of Alzheimer astrocytosis, all support this hypothesis. In most clinical studies, little if any correlations have been found between cerebral hyperintensities and neurological manifestations. The application of a test designed to evaluate patients with Parkinson's disease (where extrapyramidal signs are typical) showed significant clinical correlations both with pallidal hyperintensity and with choline/creatine ratio at 1H MRS in BG structures. Because of complex neuronal connections between BG and many cortical areas, BG dysfunction may influence the neurocognitive manifestations of hepatic encephalopathy. Similarities between chronic Mn intoxication and cirrhosis suggest common pathophysiological mechanisms including altered dopaminergic neurotransmission, although information in chronic liver failure is limited. Clinical observations are presented regarding the evolution of parkinsonian signs in various situations.
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PMID:Clinical significance of basal ganglia alterations at brain MRI and 1H MRS in cirrhosis and role in the pathogenesis of hepatic encephalopathy. 1260 16

We administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to adult, male cats to model Parkinson's disease (PD), and utilized proton magnetic resonance imaging (MRI) and spectroscopy (MRS) at a field strength of 1.5 T to identify metabolic degenerative changes in the striatum in vivo. Neurologic status and somatosensory-evoked potentials in vivo, as well as postmortem striatal histopathological and immunohistochemical parameters, were examined. Nine cats were equally divided into three groups and treated daily for 10 days as follows: saline, MPTP, and pargyline (a monoamine oxidase inhibitor) plus MPTP. The MPTP-treated cats displayed bradykinesia, head tremor, and reduced oculovestibular reflex activity. MRI showed a diffuse increase of the T2-weighted signal in the striatum of two MPTP-treated cats. Analysis of the MRS spectra indicated significantly lower N-acetylaspartate/creatine (CR) and glutamine-glutamate complex/CR ratios than the control baseline. Two MPTP-treated cats had low choline-containing compounds/CR ratio, whereas a lactate peak was present in all MPTP-treated cats. In the striatum of the MPTP-treated cats, there was a significant decline of tyrosine hydroxylase immunoreactivity and histological evidence for a diffuse cytotoxic reaction. Pretreatment with pargyline attenuated the MPTP-induced clinical signs, MRI and MRS changes, and the histopathological and immunoreactivity alterations. We conclude that proton MRI/MRS is a sensitive, noninvasive measure of neural toxicity and biochemical alteration of the striatum in a feline model of PD.
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PMID:Proton magnetic resonance imaging and spectroscopy identify metabolic changes in the striatum in the MPTP feline model of parkinsonism. 1261 22

Systems aimed at detecting gene expression noninvasively in vivo are desirable for evaluating the outcome of gene transfer in clinical trials. Several approaches have been exploited using magnetic resonance imaging and spectroscopy ((31)P MRS), positron emission tomography (PET), single-photon emission tomography (SPECT), and detection of bioluminescent signals. An ideal system is based on transfer of a marker gene, the activity of which can be detected against a background from the target tissue without interfering with normal physiology or eliciting an immune response. The majority of approaches described to date use genes encoding a nonmammalian protein that can elicit immune responses or a transmembrane receptor as a marker gene whose ectopic expression may cause aberrant signaling in the target cell through binding to endogenous ligands. The dopamine transporter (DAT) is normally expressed at high levels, mainly in the dopaminergic neurons of the central nervous system. We previously synthesized a radioactive ligand, [(99m)Tc]TRODAT-1, that binds with high affinity to the dopamine transporter, allowing for SPECT imaging of the striatum in normal control subjects and individuals affected with Parkinson's disease. Here we describe a strategy to monitor gene transfer based on adeno-associated viral vector (AAV)-mediated transduction of DAT in murine muscle followed by [(99m)Tc]TRODAT-1 imaging by SPECT of cells expressing the transgene. We show that quantitative, noninvasive imaging of gene transfer is successfully achieved in vivo, using a single-photon computed tomography camera. This system employs a reporter gene encoding a mammalian protein that is absent in most tissues, has no enzymatic activity, and does not activate intracellular pathways. This should be useful to monitor gene transfer in the settings of gene therapy.
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PMID:In vivo quantitative noninvasive imaging of gene transfer by single-photon emission computerized tomography. 1263 5

To investigate whether there are significant changes in regional brain metabolism in patients with Parkinson's disease before and after thalamotomy using proton magnetic resonance spectroscopy (1H MRS). Fifteen patients underwent 15 stereotactic thalamotomies for control of medically refractory parkinsonian tremor. Single-voxel 1H MRS was carried out on a 1.5 T unit using stimulated-echo acquisition mode (STEAM) sequence (TR/TM/TE, 2000/14/20 ms). Spectra were obtained from substantia nigra, thalamus and putamen areas with volumes of interests (7-8 ml) in patients before and after the surgery. Metabolite ratios of NAA/Cho, NAA/Cr and Cho/Cr were calculated from relative peak area measurements. We evaluated alterations of metabolite ratios in brain metabolism in Parkinson's disease patients with clinical outcome following thalamotomy. NAA/Cho ratios showed generally low levels in substantia nigra and thalamus in Parkinson's disease patients with clinical improvement following thalamotomy. In 80% (12/15) patients, decreased NAA/Cho ratios were observed from the selected voxels in substantia nigra after thalamic surgery (P<0.05). The ratios were also significantly decreased in thalamus in 67% (10/15) patients with clinical improvement (P<0.05). Our results suggest that NAA/Cho ratio may be a valuable criterion for evaluation of Parkinson's disease patients with the clinical improvement following surgery. 1H MRS may be a useful utility for the aid in better understanding the pathophysiologic process in Parkinson's disease patients on the basis of the variation of NAA/Cho ratio.
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PMID:Proton MR spectroscopic changes in Parkinson's diseases after thalamotomy. 1292 60

In spite of several evidences for a mitochondrial impairment in Parkinson's disease (PD), so far it has not been possible to show in vivo mitochondrial dysfunction in the human brain of PD patients. The authors used the high temporal and spatial resolution 31 phosphorus magnetic resonance spectroscopy (31P MRS) technique, which they have previously developed in normal subjects and in patients with mitochondrial diseases to study mitochondrial function by observing high-energy phosphates (HEPs) and intracellular pH (pH) in the visual cortex of 20 patients with PD and 20 normal subjects at rest, during, and after visual activation. In normal subjects, HEPs remained unchanged during activation, but rose significantly (by 16%) during recovery, and pH increased during visual activation with a slow return to rest values. In PD patients, HEPs were within the normal range at rest and did not change during activation, but fell significantly (by 36%) in the recovery period; pH did not reveal a homogeneous pattern with a wide spread of values. Energy unbalance under increased oxidative metabolism requirements, that is, the postactivation phase, discloses a mitochondrial dysfunction that is present in the brain of patients with PD even in the absence of overt clinical manifestations, as in the visual cortex. This is in agreement with our previous findings in patients with mitochondrial disease without clinical central nervous system (CNS) involvement. The heterogeneity of the physicochemical environment (i.e., pH) suggests various degrees of subclinical brain involvement in PD. The combined use of MRS and brain activation is fundamental for the study of brain energetics in patients with PD and may prove an important tool for diagnostic purposes and, possibly, to monitor therapeutic interventions.
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PMID:Parkinson's disease and brain mitochondrial dysfunction: a functional phosphorus magnetic resonance spectroscopy study. 1609 20

Mitochondrial dysfunction has been implicated in the death of nigrostriatal dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated experimental models of Parkinson's disease (PD). Here we utilized proton magnetic resonance spectroscopy ((1)H MRS) to identify changes in energy metabolism in the striatum of MPTP-treated C57BL/6 mice. Remarkable increases in lactate/creatine (Lac/Cr) ratio were observed at 2 h and then quickly returned to about the basal level by 7 h after injection of MPTP. Neurochemical and Western blot analyses revealed that dopamine contents and protein levels of tyrosine hydroxylase and dopamine transporter in the striatum were profoundly decreased at 3 days after MPTP treatment. Pretreatment with deprenyl, a monoamine oxidase B inhibitor, or GBR-12909, a dopamine uptake inhibitor, almost completely attenuated both the increases in striatal Lac/Cr ratio and the subsequent loss of dopaminergic nerve terminals in MPTP-treated mice. The present study indicates that (1)H MRS is a sensitive measure of biochemical alterations of the brain in a mouse model of PD, and further shows that the increases in striatal Lac/Cr ratio induced by MPTP may be associated with mitochondrial energy crisis, followed by dopaminergic neurotoxicity.
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PMID:H MRS identifies lactate rise in the striatum of MPTP-treated C57BL/6 mice. 1651 73

Neurodegeneration refers to a large clinically and pathologically heterogeneous disease entity associated with slowly progressive neuronal loss in different anatomical and functional systems of the brain. Neurodegenerative diseases often affect cognition, e.g. Alzheimer's disease (AD), dementia with Lewy bodies and vascular dementia, or different aspects of the motor system, e.g., amyotrophic lateral sclerosis, Parkinson's disease and ataxic disorders. Owing to increasing knowledge about the mechanisms leading to neurodegeneration, the development of treatments able to modify the neurodegenerative process becomes possible for the first time. Currently, clinical outcome measures are used to assess the efficacy of such treatments. However, most clinical outcome measures have a low test-retest reliability and thus considerable measurement variance. Therefore, large patient populations and long observation times are needed to detect treatment effects. Furthermore, clinical outcome measures cannot distinguish between symptomatic and disease-modifying treatment effects. Therefore, alternative biomarkers including neuroimaging may take on a more important role in this process. Because MR scanners are widely available and allow for non-invasive detection and quantification of changes in brain structure and metabolism, there is increasing interest in the use of MRI/MRS to monitor objectively treatment effects in clinical trials of neurodegenerative diseases. Particularly volumetric MRI has been used to measure atrophy rates in treatment trials of AD because the relationship between atrophic changes and neuron loss is well established and correlates well with clinical measures. More research is needed to determine the value of other MR modalities, i.e. diffusion, perfusion and functional MRI and MR spectroscopy, for clinical trials with neuroprotective drugs.
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PMID:Evaluation of treatment effects in Alzheimer's and other neurodegenerative diseases by MRI and MRS. 1698 15

Loss of nigral dopamine neurons in Parkinson's disease induces abnormal activation of glutamate systems in the basal ganglia. The purpose of this study was to assess these changes in the lentiform nucleus using MRS with optimized glutamate sensitivity (TE-averaged method). Ten patients with Parkinson's disease and 10 healthy controls were examined. Compared with healthy controls, no significant differences in glutamate were measured in patients, but a trend to lower total creatine was observed.
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PMID:Glutamate measurement in Parkinson's disease using MRS at 3 T field strength. 1733 78

Over the past decade imaging technologies employed in clinical neurosciences have significantly advanced. Imaging is not only used for the diagnostic work-up of neurological disorders but also crucial to follow up on therapeutic efforts. Using disease-specific imaging parameters, as read-outs for the efficiency of individual therapies, has facilitated the development of various novel treatments for neurological disease. Here, we review various imaging technologies, such as cranial computed tomography (CT), magnetic resonance imaging (MRI) and spectroscopy (MRS), positron emission tomography (PET) and single-photon emission computed tomography (SPECT), with respect to their current applications in non-invasive disease phenotyping and the measurement of therapeutic outcomes in neurology. In particular, applications in neuro-oncology, Parkinson's disease, Alzheimer's disease, and cerebral ischemia are discussed. Non-invasive imaging provides further insights into the molecular pathophysiology of human diseases and facilitates the design and implementation of improved therapies.
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PMID:Role of in vivo imaging of the central nervous system for developing novel drugs. 1742 Jul 17

The rapid development of transgenic mouse models of neurodegenerative diseases, in parallel with the rapidly expanding growth of MR techniques for assessing in vivo, non-invasive, neurochemistry, offers the potential to develop novel markers of disease progression and therapy. In this review we discuss the interpretation and utility of MRS for the study of these transgenic mouse and rodent models of neurodegenerative diseases such as Alzheimer's (AD), Huntington's (HD) and Parkinson's disease (PD). MRS studies can provide a wealth of information on various facets of in vivo neurochemistry, including neuronal health, gliosis, osmoregulation, energy metabolism, neuronal-glial cycling, and molecular synthesis rates. These data provide information on the etiology, natural history and therapy of these diseases. Mouse models enable longitudinal studies with useful time frames for evaluation of neuroprotection and therapeutic interventions using many of the potential MRS markers. In addition, the ability to manipulate the genome in these models allows better mechanistic understanding of the roles of the observable neurochemicals, such as N-acetylaspartate, in the brain. The argument is made that use of MRS, combined with correlative histology and other MRI techniques, will enable objective markers with which potential therapies can be followed in a quantitative fashion.
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PMID:Application of MRS to mouse models of neurodegenerative illness. 1745 Nov 83


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