ABSTRACT
Extensive changes in resting-state oscillatory brain activity have recently been demonstrated using magnetoencephalography (MEG) in moderately advanced, non-demented Parkinson's disease patients relative to age-matched controls. The aim of the present study was to determine the onset and evolution of these changes over the disease course and their relationship with clinical parameters. In addition, we evaluated the effects of dopaminomimetics on resting-state oscillatory brain activity in levodopa-treated patients. MEG background oscillatory activity was studied in a group of 70 Parkinson's disease patients with varying disease duration and severity (including 18 de novo patients) as well as in 21 controls that were age-matched to the de novo patients. Whole head 151-channel MEG recordings were obtained in an eyes-closed resting-state condition. Levodopa-treated patients (N = 37) were examined both in a practically defined 'OFF' as well as in the 'ON' state. Relative spectral power was calculated for delta, theta, low alpha, high alpha, beta and gamma frequency bands and averaged for 10 cortical regions of interest (ROIs). Additionally, extensive clinical and neuropsychological testing was performed in all subjects. De novo Parkinson's disease patients showed widespread slowing of background MEG activity relative to controls. Changes included a widespread increase in theta and low alpha power, as well as a loss of beta power over all but the frontal ROIs and a loss of gamma power over all but the right occipital ROI. Neuropsychological assessment revealed abnormal perseveration in de novo patients, which was associated with increased low alpha power in centroparietal ROIs. In the whole group of Parkinson's disease patients, longer disease duration was associated with reduced low alpha power in the right temporal and right occipital ROI, but not with any other spectral power measure. No association was found between spectral power and disease stage, disease severity or dose of dopaminomimetics. In patients on levodopa therapy, a change from the 'OFF' to the 'ON' state was associated with decreases in right frontal theta, left occipital beta and left temporal gamma power and an increase in right parietal gamma power. Widespread slowing of oscillatory brain activity is a characteristic of non-demented Parkinson's disease patients from the earliest clinical stages onwards that is (largely) independent of disease duration, stage and severity and hardly influenced by dopaminomimetic treatment. Some early cognitive deficits in Parkinson's disease appear to be associated with increased low alpha power. We postulate a role for hypofunctional non-dopaminergic ascending neurotransmitter systems in spectral power changes in non-demented Parkinson's disease patients.
Subject(s)
Biological Clocks , Brain/physiopathology , Parkinson Disease/physiopathology , Aged , Antiparkinson Agents/therapeutic use , Biological Clocks/drug effects , Cognition Disorders/etiology , Cognition Disorders/physiopathology , Dose-Response Relationship, Drug , Female , Humans , Levodopa/therapeutic use , Magnetic Resonance Imaging/methods , Magnetoencephalography , Male , Middle Aged , Neuropsychological Tests , Parkinson Disease/drug therapy , Parkinson Disease/psychology , Severity of Illness Index , Signal Processing, Computer-Assisted , Time FactorsABSTRACT
OBJECTIVES: To examine the validity of [(123)I]beta-CIT SPECT for monitoring the progression of dopaminergic degeneration in Parkinson's disease; to investigate the influence of short term treatment with D(2)receptor agonists on striatal [(123)I]beta-CIT binding; and to determine the sample size and frequency of SPECT imaging required to demonstrate a significant effect of a putative neuroprotective agent. METHODS: A group of 50 early stage Parkinson's disease patients was examined. Two SPECT imaging series were obtained, 12 months apart. The mean annual change in the ratio of specific to non-specific [(123)I]beta-CIT binding to the striatum, putamen, and caudate nucleus was used as the outcome measure. RESULTS: A decrease in [(123)I]beta-CIT binding ratios between the two images was found in all regions of interest. The average decrease in [(123)I]beta-CIT binding ratios was about 8% in the whole striatum, 8% in the putaminal region, and 4% in the caudate region. Comparison of scans done in nine patients under two different conditions-in the off state and while on drug treatment-showed no significant alterations in the expression of striatal dopamine transporters as measured using [(123)I]beta-CIT SPECT. Power analysis indicated that to detect a significant (p < 0.05) effect of a neuroprotective agent with 0.80 power and 30% of predicted protection within two years, 216 patients are required in each group when the effects are measured in the whole putamen. CONCLUSIONS: [(123)I]beta-CIT SPECT seems to be a useful tool to investigate the progression of dopaminergic degeneration in Parkinson's disease and may provide an objective method of measuring the effectiveness of neuroprotective treatments. Short term treatment with a D(2)agonist does not have a significant influence on [(123)I]beta-CIT binding to dopamine transporters. If the latter finding is replicated in larger groups of patients, it supports the suitability of [(123)I]beta-CIT SPECT for examining the progression of neurodegeneration in patients being treated with D(2)receptor agonists.
Subject(s)
Cocaine/analogs & derivatives , Nerve Degeneration/pathology , Parkinson Disease/diagnostic imaging , Parkinson Disease/pathology , Radiopharmaceuticals , Tomography, Emission-Computed, Single-Photon , Antiparkinson Agents/therapeutic use , Benzothiazoles , Caudate Nucleus/diagnostic imaging , Caudate Nucleus/metabolism , Caudate Nucleus/pathology , Corpus Striatum/diagnostic imaging , Corpus Striatum/metabolism , Corpus Striatum/pathology , Disease Progression , Female , Humans , Male , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Pergolide/therapeutic use , Pramipexole , Putamen/diagnostic imaging , Putamen/metabolism , Putamen/pathology , Receptors, Dopamine D2/metabolism , Reproducibility of Results , Thiazoles/therapeutic use , Treatment OutcomeABSTRACT
Perseveration in the generation of random motor behavior was examined by means of the Vienna perseverance task in groups of de novo (n = 18) and treated (n = 18) patients with early PD, and in control subjects (n = 18). In comparison with control subjects, both the de novo and treated patients with PD were relatively unable to generate random motor sequences, indicating a decreased ability to switch cortical behavioral programs in PD. An impairment of random motor generation appears to be a very early feature of PD.
Subject(s)
Antiparkinson Agents/therapeutic use , Parkinson Disease/diagnosis , Psychomotor Performance , Serial Learning , Stereotyped Behavior , Aged , Female , Humans , Male , Middle Aged , Neurologic Examination/drug effects , Parkinson Disease/drug therapy , Psychomotor Performance/drug effects , Reaction Time/drug effects , Serial Learning/drug effects , Stereotyped Behavior/drug effectsABSTRACT
Tremor is one of the clinical hallmarks of Parkinson's disease (PD). Although it is accepted that other classic symptoms of PD such as rigidity and bradykinesia result from a degeneration of the nigrostriatal system and subsequent reduction in striatal dopamine, the pathophysiology of resting tremor remains unclear. The majority of recent single photon emission computed tomography (SPECT) and positron emission tomography (PET) studies, using various radioligands, demonstrated significant correlation between striatal radioligand bindings and the degree of parkinsonian symptoms such as rigidity and bradykinesia, but not tremor. We investigate the relationship between the degeneration of the nigrostriatal pathway and the appearance of resting tremor, taking into account the possible interference of rigidity with the resting tremor. Thirty early and drug-naïve PD patients were examined. Tremor and rigidity of the arms were assessed using UPDRS, and the power of tremor was estimated using spectral analysis of tremor peaks. [(123)I]beta-CIT SPECT was used to assess degeneration of the dopaminergic system in PD patients. A comparison between asymmetry indices showed that in terms of both tremor and rigidity, the most affected arm corresponded significantly with the contralateral striatum, having the largest reduction in radioligand binding. Furthermore, tremor power accounted for a significant part of variance in the contralateral striatum, suggesting a relationship between this PD symptom and the degeneration of the dopaminergic system. Further, the degree of tremor was reduced with increasing rigidity. However, correcting for the influence of rigidity, the significant contribution of tremor in the variance in the contralateral striatal [(123)I]beta-CIT binding disappeared. When the confounding influence of rigidity is taken into account, no significant direct relationship between dopaminergic degeneration and the degree of tremor could be found. Other pathophysiological mechanisms should be similarly investigated in order to further our understanding of the origin of resting tremor in PD.
Subject(s)
Cocaine , Iodine Radioisotopes , Muscle Rigidity/physiopathology , Parkinson Disease/physiopathology , Tomography, Emission-Computed, Single-Photon , Tremor/physiopathology , Adult , Cocaine/analogs & derivatives , Corpus Striatum/diagnostic imaging , Dominance, Cerebral , Female , Humans , Male , Middle Aged , Parkinson Disease/diagnostic imaging , Radiopharmaceuticals , Severity of Illness Index , Tomography, Emission-Computed, Single-Photon/methodsABSTRACT
Direct and indirect signs and symptoms of Parkinson's disease are a major cause of disability in the elderly. Intrinsic symptoms comprise not only the well-known clinical hallmarks of this disease with motor behavioral abnormalities, such as bradykinesia, hypokinesia, rigidity and tremor, but also autonomic failure with orthostatic hypotension, urinal incontinence and impotence as well as non-motor behavioral abnormalities: mental dysfunction characterized by mood disorders, cognitive dysfunction and, sporadically, delusions and hallucinations. These symptoms are caused by a progressive abnormal degeneration of the dopamine (DA) producing cells in the substantia nigra (SN) and ventral tegmentum area (VTA) in combination with an interindividual fluctuating degree of decay in the noradrenergic (locus coeruleus), cholinergic forebrain (nucleus basalis of Meynert) and serotoninergic (dorsal raphe nuclei) systems. Extrinsic symptoms, induced by pharmacotherapy, mainly manifest with (un)predictable motor response fluctuations and dopaminomimetic psychosis. Psychological and psychiatric symptoms in Parkinson's disease (PD) are important predictors of the patient's quality of life. As these symptoms are potentially treatable, identification is of major clinical importance both for the patients and their caregivers and may enable to maintain Parkinson's disease patients at home for a longer period.
Subject(s)
Parkinson Disease/drug therapy , Parkinson Disease/psychology , Psychotic Disorders/drug therapy , Psychotic Disorders/etiology , Humans , Psychotic Disorders/psychologyABSTRACT
We investigated the applicability [123I]FP-CIT SPECT for the assessment of the rate of dopaminergic degeneration in PD. Twenty early-stage PD patients (age range 43-73 yr; mean age 55.4) were examined twice, a mean of 12 months apart. The mean annual change in the ratio of specific to nonspecific [123I]FP-CIT binding to the striatum was used as the outcome measure. The mean annual decrease in striatal [123I]FP-CIT binding ratios was found to be about 8% (of the baseline mean). In order to demonstrate a significant effect (p < 0.05) of putative neuroprotective agent with 0.80 power and 50% of predicted protection within 2 years, 36 patients are required in each group, when the effects are measured by means of changes in [123I]FP-CIT binding ratios in whole striatum. Our findings indicate that [123I]FP-CIT SPECT seems to be a useful tool to investigate the progression of dopaminergic degeneration in PD and may provide an objective method of measuring the effectiveness of neuroprotective therapies.
Subject(s)
Dopamine/metabolism , Neostriatum/diagnostic imaging , Neural Pathways/diagnostic imaging , Parkinson Disease/diagnostic imaging , Presynaptic Terminals/diagnostic imaging , Substantia Nigra/diagnostic imaging , Tropanes , Adult , Aged , Binding Sites/drug effects , Binding Sites/physiology , Binding, Competitive/drug effects , Binding, Competitive/physiology , Disease Progression , Female , Humans , Male , Middle Aged , Neostriatum/pathology , Neural Pathways/pathology , Neuroprotective Agents/pharmacology , Parkinson Disease/pathology , Presynaptic Terminals/pathology , Radionuclide Imaging , Substantia Nigra/pathology , Tropanes/pharmacokineticsABSTRACT
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), characterized by an autosomal dominant inheritance pattern, has recently been recognized as a distinct entity that can display a confusingly broad clinical phenotype. The pallido-ponto-nigral degeneration (PPND) variant is the prototypical example of the parkinsonism-predominant pattern of FTDP-17. A longitudinal videotape demonstration of the clinical progression of this entity in a single individual, along with brief videotape segments from three additional affected individuals, is presented in order to facilitate recognition of this disorder.
Subject(s)
Chromosomes, Human, Pair 17 , Dementia/genetics , Genetic Linkage/genetics , Parkinsonian Disorders/genetics , Adult , Dementia/diagnosis , Follow-Up Studies , Humans , Male , Middle Aged , Neurologic Examination , Parkinsonian Disorders/diagnosis , Videotape RecordingABSTRACT
By the time a clinical diagnosis of Parkinson's disease (PD) is made, a significant loss of dopaminergic neurons has already occurred. Identifying patients in the period between the presumed onset of dopaminergic cell loss and the appearance of clinical parkinsonism may be of major importance in the development of effective neuroprotective treatment strategies. In an effort to develop a feasible strategy to detect preclinical PD, a combination of olfactory processing tasks, including odor detection, odor identification, and odor discrimination was used to select groups of hyposmic and normosmic individuals from a total of 250 relatives (parents, siblings, or children) of subjects with PD. Single photon emission computed tomography (SPECT) with [123I]beta-CIT as a dopamine transporter ligand was used to assess nigrostriatal dopaminergic function in 25 hyposmic and 23 normosmic relatives of PD patients. An abnormal reduction in striatal dopamine transporter binding was found in 4 out of 25 hyposmic relatives of PD patients, two of whom subsequently developed clinical parkinsonism, and in none of the 23 normosmic relatives. These observations demonstrate that subclinical reductions in dopamine transporter binding can be detected in asymptomatic relatives of sporadic PD patients by means of [123I]beta-CIT and SPECT. The results further indicate that olfactory deficits may precede clinical motor signs in PD.
Subject(s)
Dopamine/physiology , Olfaction Disorders/genetics , Parkinson Disease/diagnostic imaging , Parkinson Disease/physiopathology , Aged , Humans , Middle Aged , Nortropanes , Parkinson Disease/genetics , Risk Factors , Task Performance and Analysis , Tomography, Emission-Computed, Single-PhotonABSTRACT
Psychosis is quite common in Parkinson's disease (approximately 25% of patients) and therefore constitutes a serious public health problem. All patients suffering from idiopathic Parkinson's disease, and especially elderly and demented patients, are at risk of developing delusions or hallucinations. The most prominent psychotogenic factors are dopaminomimetic agents, which may induce dopamine hypersensitivity in the frontal and limbic dopamine projection regions, and consequently, either directly or indirectly, elicit psychotic signs and symptoms. A Parkinson's disease-related cholinergic deficit in combination with an age-related further loss of cholinergic integrity also plays a prominent role. Psychosis in Parkinson's disease patients appears to be a more important contributor to caregiver distress than motor parkinsonism. Psychosis therefore probably represents the single greatest risk factor for nursing home placement. Typical antipsychotic drugs, because of their selective dopamine receptor antagonistic effects, can reduce psychotic signs but at the cost of an increase in parkinsonism. As a consequence of a non-selective antagonism at both serotonergic and dopaminergic receptors, atypical antipsychotic drugs are associated with fewer extrapyramidal side-effects. On the other hand, hypersensitivity to these agents may induce delirium or a malignant neuroleptic syndrome. Atypical antipsychotic agents such as clozapine, quetiapine and olanzapine should therefore be started at very low doses that are increased gradually. Cholinomimetic therapy may prove to be helpful in the prevention and treatment of psychotic manifestations in Parkinson's disease patients, given the effects observed in patients suffering from dementia with Lewy bodies.
Subject(s)
Antipsychotic Agents/therapeutic use , Neurocognitive Disorders/drug therapy , Parkinson Disease/drug therapy , Antipsychotic Agents/adverse effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Humans , PrognosisABSTRACT
[123I]FP-CIT (N-omega-fluoropropyl-2 beta-carbomethoxy-3 beta-(4-iodophenyl)nortropane) has been developed successfully as a radioligand for single-photon emission tomography (SPET) imaging of dopamine transporters, which are situated in the membrane of dopaminergic neurons. Imaging of these transporters has shown promise as a clinical tool to detect degeneration of the dopaminergic nigrostriatal pathway. Several "presynaptic parkinsonian" syndromes, such as Parkinson's disease or multiple system atrophy, are characterised by degeneration of the nigrostriatal pathway. [123I]FP-CIT SPET imaging studies have shown the ability to detect loss of striatal dopamine transporters in such syndromes. However, in clinical practice it is sometimes difficult, but important, to discriminate patients with "presynaptic parkinsonism" from those with other forms of parkinsonism not characterised by loss of presynaptic dopaminergic cells (e.g. psychogenic parkinsonism or drug-induced postsynaptic parkinsonism). In these inconclusive cases, it may be of value to confirm or exclude the existence of degeneration of nigrostriatal dopaminergic cells by using imaging techniques such as [123I]FP-CIT SPET. Using [123I]FP-CIT SPET, we have imaged the striatal dopamine transporters in a group of patients with inconclusive forms of parkinsonism, and, moreover, have been able to perform clinical follow-up of these patients 2-4 years after imaging. In 33 inconclusive cases, ratios of specific to non-specific binding were calculated for the caudate nucleus and putamen following [123I]FP-CIT SPET imaging and compared with ratios obtained in healthy controls. In nine of the patients, degeneration of the nigrostriatal pathway was found scintigraphically and in all these cases, presynaptic parkinsonism was confirmed by clinical follow-up. In the other 24 subjects no degeneration was found scintigraphically. Forms of parkinsonism other than the presynaptic were confirmed at follow-up in 19 cases, and in three cases no conclusive diagnosis was established, but presynaptic parkinsonism was excluded clinically. A clinical diagnosis of presynaptic parkinsonism was established in two cases: one case of multiple system atrophy (in this patient loss of dopamine D2 receptors was found with [123I]iodobenzamide SPET performed 2 weeks after [123I]FP-CIT imaging) and one case of Parkinson's disease. Our data suggest that the positive predictive value of [123I]FP-CIT imaging is very high, and although the negative predictive value is lower, dopamine transporter imaging offers the prospect of a quick, objective method to confirm or exclude presynaptic parkinsonism in inconclusive cases.
Subject(s)
Carrier Proteins/metabolism , Membrane Glycoproteins , Membrane Transport Proteins , Neostriatum/diagnostic imaging , Neostriatum/metabolism , Nerve Tissue Proteins , Parkinson Disease/diagnostic imaging , Parkinson Disease/metabolism , Radiopharmaceuticals , Tropanes , Adolescent , Adult , Aged , Diagnosis, Differential , Dopamine Plasma Membrane Transport Proteins , Follow-Up Studies , Humans , Image Processing, Computer-Assisted , Middle Aged , Nerve Degeneration/pathology , Receptors, Presynaptic/metabolism , Tomography, Emission-Computed, Single-PhotonABSTRACT
Olfactory dysfunction is a common finding in patients with Parkinson's disease (PD). As most studies reported on odor identification in more advanced and treated PD, we administered an odor detection, discrimination, and identification test to a heterogeneous, partly de novo, group of patients. Forty-one non-demented PD patients, 24 of whom had untreated early PD, and 18 healthy controls, were examined. Odor identification and discrimination data were corrected for odor detection scores. PD patients scored significantly lower on all olfactory tests. Interestingly, the subgroup of de novo patients with early PD also showed significant olfactory disturbances compared with healthy subjects. Within the PD group, using multiple regression analysis, we found a significant, negative correlation between odor discrimination measures and disease The present study is the first to describe decreased performance of PD patients on odor discrimination, in addition to the already well-established deficits in odor detection and identification. Furthermore, odor discrimination measures were related to disease severity, possibly indicating that at least some aspects of olfactory dysfunction in PD may be secondary to ongoing degenerative processes in PD. As significant olfactory impairments were found in early, de novo PD, olfactory tests may be useful in the early diagnosis of PD.
Subject(s)
Dopamine Agonists/therapeutic use , Olfaction Disorders/complications , Parkinson Disease/complications , Parkinson Disease/drug therapy , Adult , Aged , Female , Humans , Male , Middle Aged , Olfaction Disorders/diagnosis , Parkinson Disease/diagnosis , Severity of Illness Index , Time FactorsABSTRACT
Parkinson's disease (PD) is characterized neuropathologically by degeneration of the nigrostriatal dopaminergic pathway. With natural aging there is loss of dopaminergic cells in the substantia nigra and, consequently, loss of dopamine transporters in the striatum. It has been suggested that PD is caused by an accelerated rate of cell death. Conceptually, symptoms in idiopathic PD become apparent after a critical level of cell loss, the "symptom threshold." It has been suggested that this symptom threshold is independent of age. In this study, [123I]FP-CIT SPECT was used to assess the effect of aging on the density of striatal dopamine transporters in vivo in controls (n = 36) and early, drug-naive, patients with PD (n = 32). We found a significant age-associated decline of [123I]FP-CIT binding to striatal dopamine transporters in controls, but not in parkinsonian patients. This finding might give further support for the existence of an age-independent threshold in PD. In a subgroup of patients with hemi-PD, we found a significant loss of dopamine transporters bilaterally in the caudate nucleus and putamen. This loss was more pronounced in the putamen than in the caudate nucleus and the contralateral binding was significantly lower than the ipsilateral binding. By using age-corrected data, we estimated that in our particular patient group motor signs started when the loss of [123I]FP-CIT binding ratios in the putamen was 46-64%.
Subject(s)
Aging/metabolism , Carrier Proteins/metabolism , Membrane Glycoproteins , Membrane Transport Proteins , Neostriatum/metabolism , Nerve Tissue Proteins , Neurons/metabolism , Parkinson Disease/metabolism , Adult , Age Factors , Aged , Aging/pathology , Disease Progression , Dopamine/metabolism , Dopamine Plasma Membrane Transport Proteins , Female , Humans , Iodine Radioisotopes , Male , Middle Aged , Neostriatum/pathology , Neostriatum/physiopathology , Nerve Degeneration/metabolism , Nerve Degeneration/pathology , Nerve Degeneration/physiopathology , Neural Pathways/metabolism , Neural Pathways/pathology , Neural Pathways/physiopathology , Neurons/pathology , Parkinson Disease/pathology , Parkinson Disease/physiopathology , Sex Factors , Substantia Nigra/metabolism , Substantia Nigra/pathology , Substantia Nigra/physiopathology , Tomography, Emission-Computed, Single-Photon , TropanesABSTRACT
Parkinson's disease (PD) is an idiopathic disease caused by necrosis and apoptosis of dopaminergic cells in the brainstem, which are probably induced by oxidative stress. Current therapeutic strategies comprise symptomatic and restorative treatment. Neuroprotective treatment, however, is close to becoming reality. As neuroprotective therapy may be of particular benefit to the preclinical and/or very early PD patients, identifying patients in the early stages of the disease is a priority. Both [18F]dopa positron emission tomography (PET) and [123I]beta-CIT single photon emission computed tomography (SPECT) imaging may be useful tools in diagnosing early (preclinical) PD. As screening the whole population for preclinical PD is not realistic, one has to select subjects with a high risk for this disease. Olfactory disturbances, subtle neurocognitive dysfunction, visuomotor control abnormalities and, to a lesser degree, mood and personality disorders, have lately been suggested to precede or accompany early clinical motor hallmarks of PD. In an epidemiological study, 500 first-degree relatives of PD patients were assessed for these signs and symptoms, and [123I]beta-CIT SPECT was performed on patients in the top 10% and the bottom 10% with regard to sense of smell. In this report, the study design and initial data from this ongoing study will be presented.
Subject(s)
Olfaction Disorders/diagnosis , Parkinson Disease/diagnosis , Humans , Olfaction Disorders/physiopathology , Parkinson Disease/physiopathologyABSTRACT
Alterations in neuronal nitric oxide (NO) production may play a role in the pathophysiology of Parkinson's disease (PD) Alzheimer's disease (AD), and multiple system atrophy (MSA). The biosynthesis of NO is dependent on the availability of L-arginine, the substrate for NO-synthase (NOS), and on L-glutamate, which stimulates NO synthesis via the NMDA receptor. In this process L-citrulline is formed. We measured the levels of these amino acids in cerebrospinal fluid (CSF) of 108 PD patients, 12 AD patients, 15 MSA patients and 21 healthy subjects. A slight but statistically significant elevation of CSF L-citrulline was found in MSA patients, while CSF L-glutamate was found to be significantly decreased in AD patients. We found no significant changes in L-arginine levels. Although the relation between the CSF levels of these amino acids and neuronal NO production is still unclear, our findings suggest that AD is associated with a decrease in NO synthesis.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Arginine/cerebrospinal fluid , Citrulline/cerebrospinal fluid , Glutamic Acid/cerebrospinal fluid , Multiple System Atrophy/cerebrospinal fluid , Nitric Oxide/biosynthesis , Parkinson Disease/cerebrospinal fluid , Aged , Alzheimer Disease/physiopathology , Humans , Middle Aged , Multiple System Atrophy/physiopathology , Neurons/metabolism , Neurons/pathology , Nitric Oxide Synthase/metabolism , Parkinson Disease/physiopathologyABSTRACT
Parkinson's disease (PD) is caused by an abnormal degeneration of the dopamine (DA) producing cells in the substantia nigra (SN) and ventral tegmentum area (VTA) in combination with a varying decay of the noradrenergic (locus coeruleus), cholinergic forebrain (nucleus basalis of Meynert) and serotoninergic (dorsal raphe nuclei) systems, leading to a multitude of motor and non-motor behavioral disturbances, known as parkinsonism. Normally, main dopamine depletion is restricted to the SN region with manifest (non)motor behavioral abnormalities caused by the inability to spontaneously switch between intern-cued cortical behavioral programmes. Clinical symptoms comprise motoric abnormalities, though subtle cognitive disturbances as well as psychological dysfunction with loss of mental flexibility and reactive depressive symptoms might be seen. These symptoms might be compensated in part by externally-cued behavior.
Subject(s)
Mental Disorders/complications , Parkinson Disease/psychology , Animals , Humans , Mental Disorders/psychology , Parkinson Disease/complicationsABSTRACT
We measured total glutathione concentrations in the cerebrospinal fluid (CSF) of non-demented Parkinson's disease patients (PD; n=71), demented PD patients (PDD; n=13), multiple system atrophy patients (MSA; n=10), Alzheimer's disease patients (AD; n=17) and age-matched controls (n=21). No statistically significant differences in the mean total CSF glutathione concentrations were found between groups and dopaminomimetic treatment was not found to have any effect on total CSF glutathione levels. Our main conclusion is that total glutathione is not useful as a CSF marker for assumed oxidative stress in patients with PD, MSA or AD.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Glutathione/cerebrospinal fluid , Multiple System Atrophy/cerebrospinal fluid , Parkinson Disease/cerebrospinal fluid , Aged , Chromatography, High Pressure Liquid , Female , Humans , Male , Predictive Value of TestsABSTRACT
Patients suffering from Parkinson's disease display severe and progressive deficits in motor behavior, predominantly as a consequence of the degeneration of dopaminergic neurons, located in the mesencephalon and projecting to striatal regions. The cause of Parkinson's disease is still an enigma. Consequently, the pharmacotherapy of Parkinson's disease consists of symptomatic treatment, with in particular L-dihydroxyphenylalanine (L-DOPA) and/or dopamine receptor agonists. These induce a dramatic initial improvement. However, serious problems gradually develop during long-term treatment. Therefore, a more rational, c.q. causal treatment is needed which requires the introduction of compounds ameliorating the disease process itself. The development of such compounds necessitates (1) more information on the etiopathogenesis, i.e., the cascade of events that ultimately leads to degeneration of the dopaminergic neurons, and (2) brain imaging methods, to estimate the extent of the degeneration of the dopaminergic neurons in the living patient. This is not only important for the early diagnosis, but will also allow to monitor the effectiveness of alleged neuroprotective compounds on a longitudinal base. In this paper, etiopathogenic mechanisms are highlighted along the line of the oxidative stress hypothesis and within this framework, attention is mainly focused on the putative role of glutathione, dopamine auto-oxidation and phase II biotransformation enzymes. Especially, drugs able to increase the activity of phase II biotransformation enzymes seem to elicit a broad-spectrum (neuro)protective response and look very promising leads for the development of neuroprotective treatment strategies in Parkinson's disease. New developments in brain imaging methods (single photon emission computed tomography (SPECT) and positron emission tomography (PET)) to visualize the integrity of the striatal dopaminergic neurons in humans are highlighted as well. Especially, the introduction of radioligands that bind selectively to the dopamine transporter seems to be a significant step forward for the early diagnosis of Parkinson's disease. Performing these brain imaging studies with fixed time intervals does not only create the possibility to follow the degeneration rate of the dopaminergic neurons in Parkinson's disease but also provides the opportunity to estimate therapeutic effects of putative neuroprotective agents in the individual patient.
Subject(s)
Brain/drug effects , Diagnostic Imaging/methods , Neuroprotective Agents/therapeutic use , Parkinson Disease/drug therapy , Dopamine/metabolism , Humans , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Oxidative Stress/physiology , Parkinson Disease/diagnosis , Parkinson Disease/etiology , Treatment OutcomeABSTRACT
Dopaminomimetic agents, which were rationally designed to reverse dopamine deficits in the substantia nigra and ventral tegmental area of the parkinsonian midbrain, effectively attenuate deficits in motor and non-motor behavior thought to be elicited by dopamine deficiencies in the striatal and frontal limbic regions, respectively. On the other hand, dopaminomimetic medications may also induce perturbations in postsynaptic peptides, causing dopaminergic hypersensitivity. Drug-induced chronic dopaminomimetic psychosis afflicts about one-fifth of PD patients on dopaminergic regimens. Although the long-held mechanism for psychosis in PD is excessive stimulation of mesocorticolimbic dopamine receptors, interactions between dopamine and serotonin, as well as participation of serotonin-modulated GABAergic neurons may also contribute to the pathophysiology. Reduction or withdrawal of anticholinergic agents, amantadine, and dopamine precursors or agonists constitutes a first approach to the problem but is often insufficient. Unfortunately, typical antipsychotic agents such as haloperidol, which selectively antagonizes dopamine D-2 receptors, can induce extrapyramidal syndromes such as tardive parkinsonism. On the other hand, emerging atypical neuroleptics such as clozapine, quetiapine, and olanzapine, which antagonize 5HT-2A receptors (among others), inhibit D-2 receptors to a lesser degree and exhibit selective binding to mesolimbic (vs. striatal) dopamine receptors. The limbic selectivity of these agents appears to be of greater magnitude than that typical of risperidone. In addition, the selective antiserotonergic agent ondansetron is a prospective therapeutic option. The pharmacologic properties of these agents are explored.
Subject(s)
Antiparkinson Agents/adverse effects , Dopamine Agonists/adverse effects , Parkinson Disease/diagnosis , Psychoses, Substance-Induced/etiology , Antiparkinson Agents/therapeutic use , Dopamine Agonists/therapeutic use , Humans , Parkinson Disease/drug therapyABSTRACT
OBJECTIVES: To identify coordination changes and stability in the movements of the trunk during locomotion in Parkinson disease (PD) as a function of walking velocity. STUDY DESIGN: Comparison of treadmill locomotion with an opto-electronic tracking device. PATIENTS: Newly diagnosed patients with PD (n = 27) and a group of healthy control subjects (n = 11). RESULTS: Coordination between transversal pelvic and thoracic rotations showed significantly smaller changes in mean relative phase (p < .0001) and lower variability in relative phase (p < .0001) in the PD group. No significant differences were found in stride duration and variability in stride duration. CONCLUSIONS: The relative phase data contradict traditional notions of increased variability in motor control in PD and pinpoint the importance of the trunk in identifying axial rigidity. This discrepancy may be due to lack of control for walking velocity in earlier studies. It is concluded that systematic manipulation of walking velocity can identify coordination deficits and rigidity in trunk movement. This coordination of trunk movement can also be a sensitive measure for (early) diagnosis and the assessment of movement and pharmacological therapy in PD.