Deficiency of glutamate dehydrogenase in postmortem brain samples from parkinsonian putamen.
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Biomedical subjects
Y Agid
Publications and source records attributed to Y Agid.
Cholinergic deficiency and frontal dysfunction in Parkinson's disease.
To investigate the influence of central cholinergic deficit on cognitive function in Parkinson's disease (PD), we compared the neuropsychological performance of a group of 20 patients who were treated with anticholinergic drugs (mean daily dose, 10.2 mg) with that of a group of 20 patients who received no anticholinergics. The two groups were matched for all the variables of parkinsonism and levodopa therapy. At the dose used, there was no significant difference between the two groups of patients for intellectual, visuospatial, instrumental, and memory function. In contrast, in the group that received anticholinergics severe impairment was observed on tests believed to assess frontal lobe function. These results suggest that the lesion of the ascending cholinergic neurons, which has been demonstrated post mortem in PD, may play a role in the subcorticofrontal behavioral impairment of this disease.
Afferent Pathways↗
Tyrosine hydroxylase gene expression in human ventral mesencephalon: detection of tyrosine hydroxylase messenger RNA in neurites.
The distribution of both tyrosine hydroxylase (TH) antigen and messenger RNA was investigated in the ventral mesencephalon from human brain using a 35S-labeled human TH cDNA probe and a polyclonal TH antibody. A hybridization signal was detected not only in the perikaryon but also in the neurites, most probably dendrites, of immunoreactive neurons. In cell bodies, the level of TH mRNA varies, revealing a regional heterogeneity. In the substantia nigra of patients with Parkinson's disease the number of labeled cells was markedly reduced as compared to controls.
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Choline acetyltransferase activity and [3H]vesamicol binding in the temporal cortex of patients with Alzheimer's disease, Parkinson's disease, and rats with basal forebrain lesions.
[3H]Vesamicol binding was characterized in human brain post mortem. The number of binding sites was then determined in parallel with choline acetyltransferase activity in the temporal cortex of patients with Alzheimer's disease, demented and non-demented patients with Parkinson's disease, and in the cerebral cortex of rats with quisqualic acid lesions of the nucleus basalis magnocellularis. Whereas choline acetyltransferase activity decreased in patients with Alzheimer's or Parkinson's disease indicating loss of cholinergic innervation, the number of binding sites for [3H]vesamicol was the same as or higher than in controls. Similar results were obtained with the lesioned rats. It is suggested that the increase in binding sites may reflect compensatory regulation of the spared neurons at the level of the synaptic vesicle.
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Decreased tyrosine hydroxylase messenger RNA in the surviving dopamine neurons of the substantia nigra in Parkinson's disease: an in situ hybridization study.
Parkinson's disease is associated with a massive loss in melanized dopaminergic neurons in the substantia nigra resulting in a severe striatal dopaminergic denervation. The hyperactivity which develops in the remaining striatal dopaminergic terminals may be related to an increased rate of tyrosine hydroxylation. This could be related to changes in the level of expression of the gene coding for tyrosine hydroxylase. Thus, the detection of tyrosine hydroxylase messenger RNA was looked for at cellular levels by in situ hybridization histochemistry. Image analysis shows that the hybridization signal was significantly reduced in the surviving neurons when compared to control. The subnormal tyrosine hydroxylase messenger RNA content may express a change in level of tyrosine hydroxylase gene transcription, possibly in relation to sustained suffering of the neurons still present at late stages of the disease.
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Microtopography of D1 dopaminergic binding sites in the human substantia nigra: an autoradiographic study.
The autoradiographic distribution of D1 dopaminergic binding sites was studied in the human ventral mesencephalon using the D1 antagonist [3H]SCH 23390. [3H]SCH 23390 binding was characterized by a single class of sites with a Kd of 2.5 nM and a Bmax of 31 fmol/mg of tissue. The density of [3H]SCH 23390 binding sites was high in the substantia nigra, moderate in the ventral tegmental area and low in the peri- and retrorubral field (catecholaminergic region A8). Binding densities were similar in pars compacta and pars reticulata of the substantia nigra, except for a peak value of high [3H]SCH 23390 in the pars reticulata, at a level just ventral to a zone of hyperdensity of melanized dopaminergic neurons in the pars compacta. The anatomical organization of the human ventral mesencephalon was analysed on adjacent sections stained for acetylcholinesterase histochemistry and tyrosine hydroxylase, substance P, dynorphin B, somatostatin and methionine-enkephalin immunohistochemistry, respectively. The similarity in distribution of [3H]SCH 23390 binding sites and substance P or dynorphin B immunoreactivity suggests that D1 binding sites are mainly located on the striatonigral projections. In accordance with these results: (1) the density of [3H]SCH 23390 binding sites was reduced in the substantia nigra of a patient with Huntington's chorea, a disease associated with a degeneration of striatonigral neurons; (2) the density of [3H]SCH 23390 binding sites was unaffected in the substantia nigra of a patient with Parkinson's disease, a disorder characterized by a marked loss in nigral tyrosine hydroxylase-positive neurons. [3H]SCH 23390 binding sites showed a characteristic, heterogeneous distribution within the human ventral mesencephalon, confirming data obtained in other species. The preferential localization of D1 dopamine receptors on striatonigral projections in human brain suggests that pharmacological manipulation of these receptors modulates the activity of striatonigral pathways, thereby affecting the various outputs of the nigral complex.
Acetylcholinesterase↗
Positron emission tomography study of brain benzodiazepine receptors in Friedreich's ataxia.
Central type benzodiazepine receptors were studied in 9 patients with Friedreich's ataxia and 12 healthy subjects using positron emission tomography (PET) and [11C]Ro 15-1788, a specific antagonist of the central type benzodiazepine receptors, as radioligand. A standard PET procedure was used in 5 patients and 8 controls to obtain brain kinetics of the total binding of the radioligand. The remaining subjects were intravenously injected with a saturating dose of unlabeled Ro 15-1788, 30 minutes after the tracer injection, to determine the nondisplaceable binding of [11C]Ro 15-1788. A semi-quantitative method was used to quantify the [11C]Ro 15-1788 data. None of the quantification indices in the cerebellar hemispheres, or in the other brain areas investigated, was significantly modified in patients with Friedreich's ataxia. These findings suggest that brain benzodiazepine receptors are unaffected in Friedreich's ataxia.
Adult↗
Decreased ferritin levels in brain in Parkinson's disease.
Ferritin levels were measured in postmortem brain tissue from patients dying with Parkinson's disease [treated with L-3,4-dihydroxyphenylalanine (L-DOPA)] and from control patients. Ferritin levels were decreased in the substantia nigra, caudate-putamen, globus pallidus, cerebral cortex, and cerebellum when compared with age-matched control tissues. However, in CSF from L-DOPA-treated patients and in serum from L-DOPA-treated and untreated parkinsonian patients, ferritin levels were normal. Previous studies have suggested an increased total iron content in substantia nigra of parkinsonian brain. The failure of substantia nigra ferritin formation to be stimulated by increased iron levels suggests some defect in iron handling in this critical brain region in Parkinson's disease. The reason for decreased ferritin levels throughout the parkinsonian brain is not clear but does not seem to reflect a general system deficit in ferritin.
Brain Chemistry↗
Age-induced cognitive disturbances in Parkinson's disease.
We investigated the influence of age on the occurrence of cognitive disturbances in Parkinson's disease (PD), by evaluating neuropsychological performances in early- and late-onset groups of patients (less than 45 and greater than 65 years, respectively), individually paired for all the variables of parkinsonism and compared with age-matched controls. Cognitive disorders were limited in the early-onset PD group compared with their age-matched controls. Conversely, we found global cognitive changes, including marked frontal lobe dysfunction, in the late-onset group. This specific cognitive impairment in older patients related to a significant interaction between the aging and disease processes. Late onset seemed to compound the subtle cognitive changes associated with the disease for which the early-onset group compensated. This compounding effect of aging may explain, at least partially, the high frequency of dementia in older PD patients.
Adult↗
Catecholaminergic systems in the medulla oblongata in parkinsonian syndromes: a quantitative immunohistochemical study in Parkinson's disease, progressive supranuclear palsy, and striatonigral degeneration.
We investigated tyrosine-hydroxylase (TH)-immunoreactive neurons in the medulla oblongata corresponding to the A1 and A2 cell groups in autopsy tissue of patients with Parkinson's disease (PD) (n = 3), progressive supranuclear palsy (PSP) (n = 3), striatonigral degeneration (SND) (n = 2), and in controls (n = 4). The estimated total number of TH-positive neurons in the A1 and the A2 regions was normal in PD and PSP patients. The sparing of medullary catecholaminergic cells in PD and PSP may be related to their minor degree of melanization and the possibility that intermediate compounds associated with the oxidative catabolism of norepinephrine and epinephrine may be less cytotoxic than those generated by degradation of dopamine. Patients with SND showed a marked loss of TH-immunoreactive cells in the A1 and the A2 groups, which may contribute to the impairment of vasomotor control characteristic of the disease.
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The nigrostriatal system in Parkinson's disease.
Patterns of dopaminergic cell loss in the midbrain and patterns of mesostriatal fiber loss in the caudate nucleus and putamen are described for cases of idiopathic Parkinson's disease. Neither cell loss nor fiber loss is homogeneous. In the midbrain, quantitative analysis points to a selective vulnerability of neurons in the most heavily pigmented dopaminergic cell groups. In the striatum, a dorsolateral-to-ventromedial gradient of loss appears to characterize both the caudate nucleus and the putamen. These patterns of loss and sparing have implications both for analysis of the clinical symptoms of Parkinson's disease and for study of the etiology of this disease.
Animals↗
The efficacy of levodopa treatment declines in the course of Parkinson's disease: do nondopaminergic lesions play a role?
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Brain↗
[From posture to initiation of movement].
Purposeful motor acts are subjected to two contradictory constraints. One is to move one or several body segments toward a goal, the other is to stabilize other segments in order to maintain posture and equilibrium. One of the major tasks of the central nervous system is to coordinate posture and movement. Human posture is built up from the superposition of several "modules' from the ground to the head. Each module, tied to the next one by muscles, has its proper central and reflex regulation which permits to maintain its position in relation to the underlying one. In addition, a global regulation of posture is apparent (postural tone). Equilibrium is maintained under static conditions when the center of gravity projects onto the ground within the supporting surface (feet). Sensory error detecting signals (visual, labyrinthine, proprioceptive) are correcting, through a feedback loop, the reference regulated value according to a "postural' body schema based on "metric' and "dynamic' inputs. Corrections are continuous (and slow) or discontinuous and phasic through a repertoire of synergies allowing fast corrections. During movement performance, posture and equilibrium are stabilized by "anticipatory postural adjustments'. Some are aimed at maintaining the equilibrium notwithstanding the displacement of body segments due to the movement; others stabilize one or several segments such as the head, the trunk or the arm, which serve as reference value for the calculation of the movement trajectory and for the accurate performance of the movement. The anticipatory adjustments are learned during childhood or during training for specific tasks. The adaptative networks built up for a given movement are then controlled by the movement related command signals. The central organization of these anticipatory postural adjustments relies on central brain structures involved in movement execution and movement organization. Deficit is seen in spastic patients, to some extent in cerebellar patients. Basal ganglia and premotor areas, including the supplementary motor area, are of importance for coordination between posture and movement. This suggests that one of their function might be to stabilize posture during movement performance in order to ensure precise reaching of the goal. A specific pathology of the anticipatory postural adjustments should thus be considered.
Animals↗
Localization of copper-zinc superoxide dismutase mRNA in human hippocampus by in situ hybridization.
The cellular localization of copper-zinc superoxide dismutase (CuZn SOD) mRNA was determined in the human hippocampus by in situ hybridization with a 35S-labelled DNA probe complementary to human CuZn SOD mRNA. A positive hybridization signal was detected in pyramidal cell layers CA1-CA4 of Ammon's horn (CA), pyramidal cells of subiculum and in the granule cells of the dentate gyrus. The fact that CuZn SOD gene expression is important in neurones which are preferentially vulnerable in neurodegenerative processes such as Alzheimer's disease, suggests a role played by oxygen free radicals in the mechanism of nerve cell death.
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[Parkinson's disease: some physiopathologic aspects and clinical practice].
The lesions of Parkinson's disease chiefly involve the dopaminergic nigrostriatal tract and the great subcortical-cortical dopaminergic, noradrenergic, serotoninergic and cholinergic neuron systems. On the basis of these data, one may suggest a mechanism for some motor and mental disorders, as well as the rationale for treatment with L-dopa, the origin of its main side-effects and the classical escape phenomenon observed with this drug.
Cognition Disorders↗
Striosomes and extrastriosomal matrix contain different amounts of immunoreactive choline acetyltransferase in the human striatum.
Cholinergic neuropil and cell bodies were identified in the human striatum by immunohistochemistry carried out with a polyclonal antibody raised against choline acetyltransferase (ChAT). The cholinergic neuropil was not uniformly distributed in the striatum, and especially in the caudate nucleus ChAT-poor zones corresponding to acetylcholinesterase (AChE)-poor striosomes were identified. Striosomal organization of ChAT-positive neuropil was also detected in striatal tissue from patients who had suffered parkinsonian and choreic disorders.
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Continuous and intermittent levodopa differentially affect basal ganglia function.
The effects of continuous and intermittent levodopa treatment on behavioral and biochemical indexes of basal ganglia function were compared in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway. Animals treated for 30 days with intermittent levodopa exhibited behavioral sensitization manifested by an enhanced rotational response to apomorphine; the rotational response of rats treated with an equivalent dose of levodopa by continuous infusion did not differ from that of saline-treated controls. Dopamine receptor up-regulation in the denervated striatum relative to the intact striatum was statistically significant for D1 but not D2 receptors: This asymmetry in dopamine receptor levels was diminished following intermittent levodopa treatment. Glutamic acid decarboxylase activity, modestly elevated in all groups in the denervated striatum relative to the intact striatum, increased substantially over control values bilaterally as a result of intermittent, but not continuous, levodopa treatment. These findings suggest a relation between the schedule of chronic levodopa administration and the development of behavioral sensitization, possibly as a consequence of alterations in neuronal systems located downstream from striatal dopamine receptors. The behavioral sensitization induced by chronic, intermittent dopaminomimetic treatment may serve as a model for motor fluctuations in Parkinson's disease.
Animals↗
Striatal dopamine deficiency in Parkinson's disease: role of aging.
The striatal dopaminergic innervation was investigated postmortem in 49 control and 57 parkinsonian brains by assessing the binding of tritiated alpha-dihydrotetrabenazine ([3H]TBZOH), a specific ligand of the vesicular monoamine transporter. The density of [3H]TBZOH binding sites in the caudate nucleus of control subjects decreased significantly with age, suggesting an age-dependent reduction in striatal dopamine innervation. In contrast, an increase with the age at time of death was observed in patients with Parkinson's disease, although the density of [3H]TBZOH binding sites was subnormal. Mean values represented 26.5% and 12.7% of control values in the caudate nucleus and in the putamen, respectively. The binding of [3H]TBZOH in the caudate nucleus decreased exponentially with the duration of Parkinson's disease. The rate of [3H]TBZOH binding decrease, an index of the rate of striatal dopaminergic denervation, was about twice as high in parkinsonian patients as in controls and was not related to the age at onset of the disease. The data suggest that (1) parkinsonian symptoms appear above a threshold degeneration state corresponding to 50% of the normal innervation at the age of 60, and (2) aging does not play a major role in the process of nigrostriatal neuron degeneration in Parkinson's disease.
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