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Biomedical subjects

Y Agid

Publications and source records attributed to Y Agid.

At least 325 records · Page 18Linked to original sources
PubMed1994

Differential expression of tyrosine hydroxylase and membrane dopamine transporter genes in subpopulations of dopaminergic neurons of the rat mesencephalon.

Dopaminergic (DA) cells of the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA) display differences in their topography, biochemistry and susceptibility to pathological processes. Neuronal dopamine concentration is regulated in large part by tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine synthesis, and by the dopamine reuptake system. In the present study, TH protein, TH mRNA and dopamine membrane transporter (DAT) mRNA were quantified at cellular level in 4 arbitrary subregions of the rat ventral mesencephalon (lateral, middle, medial SNC and VTA), using in situ hybridization and immunoautoradiography. The distribution of labelling for TH protein and TH mRNA was almost superimposable and close to that of DAT mRNA in mesencephalic neurons. Lower values of cellular expression in TH protein, TH mRNA and DAT mRNA were observed in the lateral part of the SNC compared to the other subregions. TH and DAT expression were correlated in SNC but not in VTA. Indeed DA cells in this region expressed low levels of DAT mRNA in comparison to the middle and medial SNC. These results suggest a heterogeneity of DA metabolism among populations of mesencephalic cells. The relative lower expression of the DAT gene in VTA neurons suggests a less efficient dopamine reuptake capacity, which may partly account for the relative sparing of the mesolimbic system reported in Parkinson's disease and MPTP-treated animals.

Animals↗
PubMed1994

Distribution of manganese-dependent superoxide dismutase in the human brain.

The distribution of manganese-dependent superoxide dismutase, an enzyme that transforms superoxide radicals into hydrogen peroxide, was studied in the human brain post mortem using a sheep polyclonal antiserum raised against the enzyme from liver mitochondria. One band, corresponding to a protein of 22,000 mol. wt was detected in the human brain by western blot analysis. At the light-microscopy level, a punctate immunostaining was observed in the neuropil and in some but not all, glial and neuronal cell bodies. Electron-microscopy revealed that the staining was exclusively confined to the inner mitochondrial membrane. A heterogeneous distribution of manganese-dependent superoxide dismutase was observed in the human brain. In the forebrain, numerous immunostained neurons were detected in the striatum, thalamus, pallidal complex and the nucleus basalis of Meynert. In the cerebellum, only granular and Purkinje cells were immunostained. Various nuclei from the brainstem displayed superoxide dismutase immunoreactivity, including the cranial nerve nuclei, the nucleus supratrochlearis, the red nucleus, the substantia nigra, the nucleus cuneiformis and subcuneiformis, the nucleus parabigeminal, the nucleus centralis superior, the nucleus supraspinalis, the nucleus of the medullae oblongata and the gigantocellularis nucleus. Large pyramidal neurons containing superoxide dismutase were detected in the CA subsectors, the hilus of the hippocampus and the cerebral cortex. Smaller immunostained neurons were also observed in layers I, IV and VI of all cortical regions studied. The distribution of immunostained glial cells was more limited, and restricted to the internal and external capsules, the hypothalamus, the red nucleus, the pyramidal white matter and surrounding areas, the cerebral cortex and the sub-ependymal layer, the alveus and the stratum oriens of the hippocampus. This heterogeneous but not ubiquitous distribution of cells expressing manganese-dependent superoxide dismutase suggests that not all cells in the human brain are protected to the same extent against the deleterious effects of superoxide.

Aged↗
PubMed1994

Immunohistochemical study of catechol-O-methyltransferase in the human mesostriatal system.

The cellular localization of catechol-O-methyltransferase was analysed in the mesostriatal system of human brain post mortem by means of immunohistochemistry. In the human nigral complex, catechol-O-methyltransferase immunostaining was not detected in melanized dopaminergic neurons, except in the ventral tegmental area and substantia nigra pars lateralis, where few neurons displayed intense immunolabelling. In the striatum, catechol-O-methyltransferase immunostaining was found in numerous cell bodies and in the neuropile. Observations at the electron microscope level revealed that catechol-O-methyltransferase immunoreactivity was present in the cell bodies of neurons and their processes, including the dendritic spines. No catechol-O-methyltransferase immunolabelling was observed in striatal nerve terminals in contact with dendritic spines, indicating that dopaminergic nerve terminals do not exhibit catechol-O-methyltransferase immunoreactivity. Catechol-O-methyltransferase-immunoreactive cell bodies and processes of glial cells were also detected in the striatum. The data suggest that catechol-O-methyltransferase is either not expressed or only slightly expressed by the dopaminergic nigrostriatal neurons, whereas it is clearly present in striatal neurons and glial cells. Thus, the catabolic degradation of striatal released dopamine by its O-methylation may involve postsynaptic neurons rather than dopaminergic presynaptic neurons. The presence of catechol-O-methyltransferase in some dopaminergic neurons of the ventral tegmental area and substantia nigra pars lateralis suggests that methylation of dopamine may occur in these neurons, which may consequently be better protected against dopamine auto-oxidation than those of the substantia nigra pars compacta.

Animals↗
PubMed1994

Somatostatin messenger RNA-containing neurons in Alzheimer's disease: an in situ hybridization study in hippocampus, parahippocampal cortex and frontal cortex.

The level of expression of somatostatin messenger RNA-containing neurons in human brain was visualized and quantified by in situ hybridization with a 35S-labelled oligonucleotide complementary to amino acids 96-111 of the preprosomatostatin complementary DNA sequence. The analysis was carried out in the frontal and parahippocampal cortices and hippocampus of six age- and post mortem delay-matched Alzheimer's disease and control brains. By northern blot analysis, in frontal cortex samples, 18S rRNA degradation was identical in control and Alzheimer brains and somatostatin messenger RNAs migrated as a single band of 1 kb. By in situ hybridization, specificity was demonstrated by abolition of the signal using either an excess of unlabelled antisense probe or using a labelled sense probe. Somatostatin messenger RNA-containing neurons displayed a similar regional and subregional distribution in control subjects and patients with Alzheimer's disease, being more abundant in the frontal cortex, followed by the hippocampus and the parahippocampal cortex. An overall reduction of labelled cell density was observed in patients with Alzheimer's disease (frontal cortex gray matter:--41%; white matter:--66%; hippocampus:--44%; parahippocampal cortex white matter:--40%). Due to a great variation between brains, this decrease only reached significance in the parahippocampal cortex (-59%, P < 0.05). A significantly lower level of expression of somatostatin messenger RNA per somatostatinergic cell was observed in the hippocampus of Alzheimer's disease patients (-47%, P < 0.05), but not in frontal cortex gray (-17%) and white (-36%) matter and parahippocampal cortex gray (-42%) and white (-29%) matter. These data are in accordance with the distribution of somatostatin cells as visualized by immunohistochemistry in human brain. They indicate that the ability of cortical cells to express somatostatin messenger RNA is partially preserved in Alzheimer disease brains and that the decrease in the amount of somatostatin messenger RNA per cell is restricted to the hippocampal formation.

Aged↗
PubMed1994

Explicit memory, procedural learning and lexical priming in Alzheimer's disease.

Different aspects of memory functions were studied in two groups of patients with Alzheimer's disease (AD) and in normal elderly controls. The tests included: explicit memory tests with free and cued recall, and recognition measures; learning of a motor skill; learning of a perceptual skill with verbal material; a priming task with the word stem completion paradigm. The data confirmed that, besides severe impairment for all measures of explicit memory, AD patients were able to learn and retain normally a motor skill in the rotor pursuit task, even across a long retention interval. Moreover, sparing of procedural learning was not restricted to motor tasks, since patients learned normally a mirror-reading task, demonstrating (a) rapid acquisition of the procedure, and (b) acquisition of item-specific information for repeated words. This last effect is accounted for in terms of repetition priming effects rather than of explicit memory strategies, since patients had also normal repetition effect in the word stem completion paradigm.

Aged↗
PubMed1994

Linkage of a new locus for autosomal dominant familial spastic paraplegia to chromosome 2p.

Autosomal dominant familial spastic paraplegia (AD-FSP) is a genetically heterogeneous neurodegenerative disorder characterized by a spasticity of the lower limbs. A locus causing AD-FSP (FSP1) has been previously mapped to chromosome 14q. We now report linkage of a second AD-FSP locus (FSP2) to chromosome 2p21-p24 in five of seven French families and one large Dutch pedigree. The analysis of recombination events and multipoint linkage place FSP2 within a 4 cM interval flanked by loci D2S400 and D2S367.

Adolescent↗
PubMed1994

Relation of anosognosia to frontal lobe dysfunction in Alzheimer's disease.

A self-rating scale of memory functions was administered to 24 non-depressed patients with probable Alzheimer's disease, divided into two groups according to the overall severity of dementia (mild, mini-mental state (MMS) > 21; moderate, MMS between 10 and 20). These groups did not significantly differ in their self-rating of memory functions. The same questionnaire was submitted to a member of each patient's family, who had to rate the patient's memory. An "anosognosia score" was defined as the difference between patient's and family's ratings. This score was highly variable, and covered, in the two groups, the full range between complete awareness of deficits and total anosognosia. Correlations between the anosognosia score and several neuropsychological data were searched for. No significant correlation was found with either the Wechsler memory scale, the MMS, or linguistic abilities and gestures. In contrast, this score was highly correlated with the "frontal score", defined as the sum of scores on the Wisconsin card sorting test (WCST), verbal fluency, Luria's graphic series, and "frontal behaviours" (prehension, utilisation, imitation behaviours, inertia, indifference). Among these tests of executive functions, the highest correlation with the anosognosia score was obtained on the WCST. This suggests that anosognosia in Alzheimer's disease is not related to the degree of cognitive deterioration but results, at least in part, from frontal dysfunction.

Aged↗
PubMed1994

Hereditary neuralgic amyotrophy and hereditary neuropathy with liability to pressure palsies: two distinct clinical, electrophysiologic, and genetic entities.

Hereditary neuralgic amyotrophy (HNA) is an autosomal disease characterized by painful episodes of brachial palsy. The presence of tomacula in some patients suggested that HNA might be genetically related to hereditary neuropathy with liability to pressure palsies (HNPP), caused by point mutations in the PMP22 gene or deletion of the region containing this gene. In a clinical, electrophysiologic, and molecular study of two families with HNA, we show that the PMP22 gene is not deleted, duplicated, or mutated in HNA and that the disease is not linked to any other gene in the HNPP deleted region. We conclude that HNA and HNPP are distinct genetic entities.

Adolescent↗
PubMed1994

Impaired simultaneous cognitive task performance in Parkinson's disease: a dopamine-related dysfunction.

Patients with Parkinson's disease (PD) have trouble programming two separate motor acts concurrently. We tested the hypotheses that (1) PD patients may also have difficulty processing two cognitive tasks simultaneously, and (2) the expected deficit may be related to the striatal dopaminergic depletion. We used auditory and visual choice reaction time (CRT) tasks, presented either separately or concurrently, and compared the performance of three groups of PD patients: a group of patients under their usual dose of levodopa ("standard"); a group assessed both at the time of maximal clinical benefit ("on" state) and at the time of minimal clinical benefit (treatment withdrawn for about 18 hours; "off" state); and a group of recently diagnosed untreated patients ("de novo"). Compared with controls, standard and "on" state patients had a normal performance for both separate and concurrent CRT tasks. In contrast, "off" state and de novo patients had a normal performance in the separate CRT tasks but significant deficits in the concurrent CRT tasks. These results suggest that adequate dopaminergic transmission is necessary for concurrent processing of cognitive information and that the striatum integrates the sensorimotor information required to program cognitive acts.

Acoustic Stimulation↗
PubMed1994

Role of pontine nuclei damage in smooth pursuit impairment of progressive supranuclear palsy: a clinical-pathologic study.

We performed a quantitative study of the pontine nuclei in the basis pontis and a semiquantitative study of extrapontine structures involved in smooth pursuit in four patients with severe impairment of horizontal smooth pursuit and histopathologically confirmed diagnosis of progressive supranuclear palsy (PSP). There were only slight changes in the extrapontine structures involved in smooth pursuit, but there was a significant neuronal loss--massive in three patients and mild in one patient--in all nuclei of the basis pontis. Our results suggest that degenerative lesions affecting the pontine nuclei are largely responsible for the horizontal smooth pursuit impairment in PSP.

Aged↗
PubMed1994

Are explicit memory disorders of progressive supranuclear palsy related to damage to striatofrontal circuits? Comparison with Alzheimer's, Parkinson's, and Huntington's diseases.

To test the hypothesis that memory disorders of subcortico-frontal dementia result mainly from inefficiency of retrieval processes of stored information, we compared verbal learning in 15 patients with progressive supranuclear palsy, prototypical of "subcortical dementia," in free (California Verbal Learning Test) and controlled (Grober and Buschke's Test) encoding situations, with that of 19 controls, matched for age and level of education. The progressive supranuclear palsy patients showed memory deficits characterized by impaired immediate memory span, disturbed learning and consistency of recall, and abnormal number of false alarms at recognition, which were dramatically alleviated by controlled encoding associated with cued recall, using the same semantic cues. This memory profile was markedly different from that of patients with senile dementia of the Alzheimer type (n = 15), characterized by more rapid forgetting and less improvement in the controlled situation. Instead, it was similar to the memory pattern of patients with Parkinson's (n = 15) and Huntington's (n = 15) diseases. These results show a similar profile of memory disturbance in disorders involving damage to the striatofrontal system and suggest that the cortical and hippocampal lesions of PSP patients are insufficiently severe to interfere with the specific memory profile characteristic of the disease.

Aged↗
PubMed1994

The phenotype of "pure" autosomal dominant spastic paraplegia.

We studied 23 families with "pure" autosomal dominant spastic paraplegia. Examination of 142 at-risk individuals allowed identification of 70 patients, including 12 who were clinically affected but unaware of symptoms. The frequency of lower limb muscle weakness, decreased vibration sense, hyperreflexia in the upper limbs, and sphincter disturbances increased with the disease duration. The distribution of age at onset was unimodal, with a mean onset of 29 years (range, 1 to 68). The clinical manifestations of "early-onset" (< 29 years) and "late-onset" (> 29 years) patients were not significantly different. Age at onset varied as much within families as among families; anticipation and imprinting did not occur. No clinical criteria allowed differentiation among the families studied. Only linkage studies can provide accurate classification of this disease.

Adult↗
PubMed1994

Clinical and genetic analysis of a Tunisian family with autosomal dominant cerebellar ataxia type 1 linked to the SCA2 locus.

Autosomal dominant cerebellar ataxias (ADCA) type 1 are a clinically and genetically heterogeneous group of neurodegenerative disorders. We report a large Tunisian ADCA type 1 family in which 17 patients (mean age at onset +/- SD = 35.6 +/- 15.3 years) were examined. There was mean anticipation of 10.3 +/- 15.4 years in this family; anticipation was greater in paternal (28 +/- 8.2 years) than in maternal (2.7 +/- 10.9 years) transmission. Linkage analysis performed with microsatellite markers linked to the spinal cerebellar ataxia 1 (SCA1) locus on chromosome 6p and the SCA2 locus on chromosome 12q excluded linkage to SCA1, but there was close linkage with marker D12S105 (Zmax = 2.51 at theta = 0.00). This result was confirmed by multipoint analysis, which generated a maximal lod score of 3.46 at this locus. Multipoint analysis and haplotype reconstruction reduced the interval containing the SCA2 locus to 6.4 cM, a narrowing of the 35-cM interval in a previously described Cuban SCA2 family with a clinical picture similar to that of our family, including a high frequency of postural and action tremor.

Adult↗
PubMed1994

Do parkinsonian symptoms and levodopa-induced dyskinesias start in the foot?

Parkinsonian symptoms and levodopa-induced dyskinesias (LIDs) are often considered to occur first, and to predominate, in the upper limbs. We studied the topography, type, sequence, and severity of LIDs in 20 consecutive patients with Parkinson's disease (PD) experiencing LIDs for less than 6 months (Hoehn and Yahr stage II-III; average age at onset of PD, 57 years; average duration of PD, 7.2 years; percent of improvement with levodopa > 50) and compared them with the initial site, form, and evolution of the patient's motor disability. Parkinsonism started in the foot in six of 20 patients. Motor disability in the "off" state was similar in upper and lower extremities, except for akinesia, which was worse in the lower limbs. A careful interview indicated that LIDs had started in the foot in all patients. After administration of a single dose of levodopa ("levodopa test"), LIDs appeared in all patients as dystonia of the foot homolateral to the side most affected by PD (onset-of-dose dyskinesia). LIDs were preceded by "off" dystonia (dystonic foot) in six patients and were followed by mid-dose dyskinesia in eight. This is consistent with an early loss of dopaminergic innervation corresponding somatotopically to the foot area. The similarities among initial LIDs, early morning dystonia, and onset-of-dose dyskinesia suggest a similar pathophysiology.

Adult↗