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Biomedical subjects

Y Agid

Publications and source records attributed to Y Agid.

At least 217 records · Page 12Linked to original sources
PubMed1996

The mental representation of hand movements after parietal cortex damage.

Recent neuroimagery findings showed that the patterns of cerebral activation during the mental rehearsal of a motor act are similar to those produced by its actual execution. This concurs with the notion that part of the distributed neural activity taking place during movement involves internal simulations, but it is not yet clear what specific contribution the different brain areas involved bring to this process. Here, patients with lesions restricted to the parietal cortex were found to be impaired selectively at predicting, through mental imagery, the time necessary to perform differentiated finger movements and visually guided pointing gestures, in comparison to normal individuals and to a patient with damage to the primary motor area. These results suggest that the parietal cortex is important for the ability to generate mental movement representations.

Adult↗
PubMed1996

Regional and cellular presenilin 2 (STM2) gene expression in the human brain.

Presenilin 2 (STM2) is a recently cloned gene involved in some forms of early onset Alzheimer's disease with autosomal dominant inheritance. Here we report the regional and cellular distribution of STM2 mRNA in the normal human central nervous system. Using in situ hybridization. STM2 gene expression was shown to be confined exclusively to neurones in the central nervous system. A high level of STM2 mRNA expression was observed in the cerebral cortex and the hippocampus, more particularly on pyramidal neurones of Ammon's horn and granular neurones of the dentate gyrus. STM2 mRNA was also detected in Purkinje cells and granular cells of the cerebellum, and in neurones of the striatum and the nucleus basalis of Meynert. Taken together, these results suggest that the expression of STM2 mRNA is not restricted to the neuronal populations that are known to degenerate in Alzheimer's disease.

Aged↗
PubMed1996

A novel presenilin 1 mutation resulting in familial Alzheimer's disease with an onset age of 29 years.

We have identified a novel Alzheimer's disease family in which affected subjects had a very young age of onset (range 29-35 years). Neuropathological confirmation of the diagnosis was obtained for one patient. Molecular analysis shows that within this family the disease results from a missense mutation at codon 235 of the presenilin 1 (PS-1) gene. Two patients had exhibited generalized tonico-clonic seizures several years before the onset of dementia. Whether this particular clinical feature is a consequence of the PS-1 mutation remains to be established. The Leu235Pro mutation is, to our knowledge, the PS-1 mutation associated with the youngest age of AD onset, which suggests that it has a drastic effect on PS-1 function.

Adult↗
PubMed1996

Expression of glutamate receptors in the human and rat basal ganglia: effect of the dopaminergic denervation on AMPA receptor gene expression in the striatopallidal complex in Parkinson's disease and rat with 6-OHDA lesion.

The overactivity of subthalamopallidal and corticostriatal glutamatergic neurons observed in Parkinson's disease (PD) suggests that antagonists of glutamate receptor could be used to alleviate the motor symptoms of the disease. In this study, we analysed two features of the striatopallidal complex: (1) the distribution of alpha-amino-3 hydroxy-5-methyl-4-isoxasol-propionate (AMPA) and kainate receptors and their corresponding mRNA by immunohistochemistry and in situ hybridisation and (2) the effect of dopaminergic denervation on AMPA receptor gene expression in PD patients and rats with 6-hydroxydopamine (6-OHDA)-induced degeneration of the nigrostriatal dopaminergic system. All AMPA receptor mRNAs and proteins (GluR1-4) were detected in the internal segment of the globus pallidus (GPi). Among kainate receptors, only KA1 and KA2 were detectable and only at a low level. Only GluR4 protein was detected in the neuropil of the GPi. In the striatum, GluR1, GluR2, and GluR3 were detected in about 70% of medium-sized and large neurons. By contrast, GluR4 mRNA was detected in only a small number of large and medium-sized neurons. Among kainate receptors, GluR6, GluR7, and KA2 were detected in about 50-60% of medium-sized neurons, whereas GluR5 and KA1 were restricted to 1-2% and 20-30% of these neurons, respectively. These results suggest that antagonists of AMPA and kainate receptors could be effective in alleviating motor symptoms in Parkinson's disease by blocking the overstimulation of pallidal and striatal neurons by glutamate. A significant decrease in GluR1 gene expression (-33%) was observed in the neurons of the GPi in PD patients and in rat entopeduncular nucleus ipsilateral to the 6-OHDA lesion (-20%). GluR2, GluR3, and GluR4 mRNA levels in the GPi and GluR1-4 levels in the striatum were unchanged in PD patients and 6-OHDA-lesioned rats compared with their respective controls. These data suggest that dopamine positively regulates only GluR1 gene expression in the GPi.

Animals↗
PubMed1996

Dopaminergic sprouting in the rat striatum after partial lesion of the substantia nigra.

The capacity of the dopaminergic nerve system to reinnervate the denervated adult striatum was analyzed in a model of partial 6-hydroxydopamine-induced unilateral lesion of rat substantia nigra pars compacta. Sprouting of dopaminergic fibers entering the ventrolateral part of the striatum from a narrow zone of the external capsule was detected on the lesioned side 4 and 7 months, but not 10 days, after lesioning. Ultrastructural examination of the zone of sprouting revealed hypertrophic dopaminergic fibers and growth-cone-like structures, confirming the existence of an ongoing process of spontaneous regrowth of dopaminergic fibers. The identification of the factors involved in the regrowth of dopaminergic fibers may help to orientate molecular research into new treatments for Parkinson's disease.

Animals↗
PubMed1996

Segregation analysis of Alzheimer pedigrees: rare Mendelian dominant mutation(s) explain a minority of early-onset cases. French Alzheimer Collaborative Group.

Segregation analysis of Alzheimer disease (AD) in 92 families ascertained through early-onset ( < or = age 60 years) AD (EOAD) probands has been carried out, allowing for a mixture in AD inheritance among probands. The goal was to quantify the proportion of probands that could be explained by autosomal inheritance of a rare disease allele "a" at a Mendelian dominant gene (MDG). Our data provide strong evidence for a mixture of two distributions; AD transmission is fully explained by MDG inheritance in < 20% of probands. Male and female age-of-onset distributions are significantly different for "AA" but not for "aA" subjects. For "aA" subjects the estimated penetrance value was close to 1 by age 60. For "AA" subjects, it reaches, by age 90, 10% (males) and 30% (females). We show a clear cutoff in the posterior probability of being an MDG case.

Age Factors↗
PubMed1996

Striatopallidal and thalamic dystonia. A magnetic resonance imaging anatomoclinical study.

OBJECTIVE: To determine which brain structures are involved in symptomatic unilateral dystonia caused by localized cerebral infarction. DESIGN: Three-dimensional T1-weighted magnetic resonance imaging sequence and stereotactic analysis were used to analyze the topography of the lesions. Stereotactic localization of thalamic lesions was conducted according to the atlas of Hassler with a Voxtool software (Advantage Windows Workstation, General Electric, Milwaukee, Wis) workstation system. PATIENTS: Eight patients with hemidystonia, segmental dystonia, or focal dystonia were selected from among 51 consecutive patients (between January 1988 and May 1993) with symptomatic unilateral dystonia. RESULTS: Patients had dystonic spasms (n=4) or myoclonic dystonia (n=4). Lesions associated with dystonic spasms were located in the striatopallidal complex, and those with myoclonic dystonia were in the thalamus contralateral to the dystonia. Lesions of the striatopallidal complex involved the putamen posterior to the anterior commissure in all patients and extended variably into the dorsolateral part of the caudate nucleus, the posterior limb of the internal capsule, or the lateral segment of the globus pallidus. These lesions were centered in the "sensorimotor" part of the striatopallidal complex, with a trend toward a somatotopical distribution. Lesions of the thalamus were located in the ventral intermediate and ventral caudal nuclei, while the ventral oral anterior and posterior nuclei (which receive pallidal efferents) were largely spared. CONCLUSIONS: These results suggest that striatopallidal and thalamic dystonia may have different pathophysiologic bases.

Adolescent↗
PubMed1996

Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features.

Patients with spinocerebellar ataxia 3 (SCA3) and Machado-Joseph disease (MJD) carry an expanded CAG repeat in the MJD1 gene. One hundred twenty families of different geographic origin with autosomal dominant cerebellar ataxia (ADCA) type I were tested. Thirty-four families (126 patients) carried an expanded CAG repeat. The expanded and the normal allele did not overlap and the repeat was unstable during transmission, with variation in the size of the CAG length ranging from -8 to +5 and a mean expansion of 0.86 repeats without differences according to the parental sex. There was a combined effect of the number of CAG repeats of the expanded and normal allele on the age at onset, which accounted for 70% of its variability. The length of the CAG repeat influenced the frequency of clinical signs associated with cerebellar ataxia, such as abnormal tendon reflexes or decreased vibration sense, whereas the interindividual variation of supranuclear ophthalmoplegia, sphincter and swallowing difficulties, and amyotrophy was mostly determined by different disease durations. We compared the clinical profile of 91 SCA3/MJD patients with 51 SCA1 and 32 SCA2 patients. There were striking differences between the SCA3/MJD and SCA2 but not with SCA1 groups of patients. Despite their clinical similarities, distinct neuropathological features were observed in 2 SCA3/MJD and 2 SCA1 patients.

Adult↗
PubMed1996

Clinical and pathological features in hydrocarbon-induced parkinsonism.

A neuropathological examination was performed on a patient with parkinsonism induced by prolonged exposure to a mixture of aliphatic hydrocarbons, mainly n-hexane and halogenated compounds. The patient developed a rapid-course disease that progressed even after withdrawal from the toxic exposure. Pathological examination and immunohistochemical analysis of the brain revealed severe and widespread dopaminergic neuronal loss, associated with severe gliosis, in the substantia nigra, and almost complete loss of tyrosine hydroxylase immunostaining in the striatum. No Lewy bodies were detected. Neuronal loss was also observed in the periaqueductal gray matter, locus ceruleus, and pedunculopontine nucleus. These changes, combined with the moderate anemia due to marrow suppression, and the mild axonal neuropathy observed in vivo, are suggestive of a hydrocarbon toxic insult.

Female↗
PubMed1996

Synaptic plasticity in the caudate nucleus of patients with Parkinson's disease.

The loss of dopaminergic neurons from the substantia nigra in Parkinson's disease (PD) may provoke a reorganization of cellular interactions in the nigrostriatal pathway. Indeed, a plasticity of putative corticostriatal synapses has been evidenced in the striatum of rats with a 6-hydroxy-dopamine-induced lesion of the substantia nigra. However, to our knowledge, synaptic plasticity in the striatum has not previously been investigated in human PD. In this study, we have analysed, at electron microscope level, the morphological characteristics of the synapses formed by afferents in asymmetric contact with dendritic spines of neurons in the caudate nucleus of three patients with PD and three matched controls. The length of the postsynaptic densities and the number of perforated synapses were both significantly increased (24 and 88%, respectively) in the PD patients; the size of these afferents and the surface area occupied by their mitochondria also showed an increase (24 and 50%, respectively), although not statistically significant. The size and density of dendritic spines and the size of postsynaptic density perforations were unchanged. These data indicate the presence of plasticity of the putative corticostriatal synapses in PD and suggest a hyperactivity of cortical afferents to GABAergic neurons.

Aged↗
PubMed1996

Cognitive deficits in non-Alzheimer's degenerative diseases.

Although observed in various brain disorders, dementia is particularly frequent in neurodegenerative diseases. Alzheimer's disease is characterized by the association of progressive amnesia with either instrumental (aphasia, apraxia, agnosia) or behavioral (apathy, indifference, anosognosia) disorders, depending upon the location of the underlying neuronal lesions. By contrast, memory, linguistic, praxic, visuo-spatial or comportemental impairments are dissociated in more focal "lobar" atrophies, while planning and retrieval deficits predominate in movement disorders with dementia. Alzheimer's and non-Alzheimer's neurodegenerative diseases can therefore be distinguished insofar as the severity and location of the associated neuronal lesions differ. Dementia may be observed in various brain diseases, either vascular, metabolic, demyelinating, traumatic, infectious, inflammatory, neoplastic or hydrocephalus (Chui, 1989). It is particularly frequent in neurodegenerative diseases. The recent clinical description of focal lobar atrophies (Weintraub and Mesulam, 1993) and the analysis of cognitive impairment observed in diseases with movement disorders (Cummings and Benson, 1984) have changed the conception of dementia, that may no more be defined as a global deterioration of higher cortical functions. The relative specificity of the cognitive picture of each disease depends on the location of the underlying neuronal lesions. Together with other tools, such as the neurological examination or the functional imagery, the neuropsychological exam may contribute to characterize the clinical picture of a patient with non-Alzheimer's degenerative disease and therefore to determine a clinical diagnosis, that remains probable till the neuropathological confrontation.

Alzheimer Disease↗
PubMed1996

Glial cell line-derived neurotrophic factor (GDNF) gene expression in the human brain: a post mortem in situ hybridization study with special reference to Parkinson's disease.

Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for dopaminergic neurons. Since dopaminergic neurons degenerate in Parkinson's disease, this factor is a potential therapeutical tool that may save dopaminergic neurons during the pathological process. Moreover, a reduced GDNF expression may be involved in the pathophysiology of the disease. In this study, we tested whether altered GDNF production may participate in the mechanism of cell death in this disease. GDNF gene expression was analyzed by in situ hybridization using riboprobes corresponding to a sequence of the exon 2 human GDNF gene. Experiments were performed on tissue sections of the mesencephalon and the striatum from 8 patients with Parkinson's disease and 6 control subjects matched for age at death and for post mortem delay. No labelling was observed in either group of patients. This absence of detectable expression could not be attributed to methodological problems as a positive staining was observed using the same probes for sections of astroglioma biopsies from human adults and for sections of a newborn infant brain obtained at post-mortem. These data suggest that GDNF is probably expressed at a very low level in the adult human brain and its involvement in the pathophysiology of Parkinson's disease remains to be demonstrated. GDNF may represent a powerful new therapeutic agent for Parkinson's disease, however.

Aged↗
PubMed1996

Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies): genetic analysis of three unrelated SCA2 families.

Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders that are clinically and genetically heterogeneous. We report here a genetic linkage study, with five chromosome 12q markers, of three Martinican families with ADCA type 1, for which the spinocerebellar ataxia 1 (SCA1) locus was excluded. Linkage to the SCA2 locus was demonstrated with a maximal lead score of 6.64 at theta = 0.00 with marker D12S354. Recombinational events observed by haplotype reconstruction demonstrated that the SCA2 locus is located in an approximately 7-cM interval flanked by D12S105 and D12S79. Using the z(max)-1 method, multipoint analysis further reduced the candidate interval for SCA2 to a region of 5 cM. Two families shared a common haplotype at loci spanning 7 cM, which suggests a founder effect, whereas a different haplotype segregated with the disease in the third family. Finally, a mean anticipation of 12+/-14 years was found in parent-child couples, with no parental sex effect, suggesting that the disease might be caused by an expanded and unstable triplet repeat.

Adolescent↗
PubMed1996

Progressive supranuclear palsy: a clinicopathological study of 21 cases.

The symptoms and signs used to diagnose progressive supranuclear palsy (PSP) should be easily identifiable by neuropathologists and neurologists as well as by movement disorder experts. The presence, at the time of death, of symptoms and signs that are used in published clinical criteria for the diagnosis of this disorder was searched for in 21 pathologically confirmed typical PSP cases. The following items, present in at least 80% of pathologically confirmed cases, can be considered as the most accurate clinical data for the diagnosis of PSP: non-familial parkinsonism, not improved by L-dopa therapy, with vertical voluntary gaze palsy; postural instability and falls; pseudobulbar palsy and dementia with frontal lobe-like syndrome; and a progressive course of less than 10 years. The definite diagnosis of PSP must be clinicopathological, and these minimal clinical data may be used for this purpose.

Adult↗
PubMed1996

Cellular distribution of the iron-binding protein lactotransferrin in the mesencephalon of Parkinson's disease cases.

Changes in the distribution of the iron-binding protein lactotransferrin have recently been described in the central nervous system during a variety of neurodegenerative disorders. To investigate whether lactotransferrin is associated with the neuropathological changes that characterize Parkinson's disease, we analyzed the distribution of this protein in the mesencephalon of neurologically normal individuals and patients affected with Parkinson's disease using quantitative immunohistochemical methods. High levels of lactotransferrin were observed in a large population of neurons in the substantia nigra of control cases. Lactotransferrin-positive neurons were severely affected by the neurodegenerative process that occurs in Parkinson's disease as indicated by a severe decrease in the number of immunolabeled neurons in all of these cases. Quantitative analysis also demonstrated higher immunolabeling levels of lactotransferrin in the surviving neurons in the substantia nigra and ventral tegmental area of Parkinson's disease cases compared to control cases. These results suggest that lactotransferrin may participate actively in the mechanism of neuronal degeneration in Parkinson's disease.

Aged↗
PubMed1996

Memory for spatial location is affected in Parkinson's disease.

Are the striato-frontal neuronal circuits implicated in learning of item-specific spatial coordinates? To answer this question, we compared the performance of 20 patients with Parkinson's disease to that of 14 controls matched for age, global cognitive efficiency and mood, on a visuo-spatial learning task with little involvement of motor and constructive functions, allowing control of encoding and comparison of free recall, cued recall and recognition. Compared to controls, patients showed a severe memory impairment for visuo-spatial location of pictures, contrasting with relative preservation of verbal memory, and mild difficulties in perceptive visuo-spatial and executive functions. These results implicate striato-frontal neuronal circuits in memory for spatial location.

Aged↗
PubMed1996

Delayed response tasks in basal ganglia lesions in man: further evidence for a striato-frontal cooperation in behavioural adaptation.

To determine the respective contribution of the subcortical structures and the prefrontal cortex in behavioural adaptation, we applied the delayed response paradigm, considered as a functional marker of the dorsolateral region of the prefrontal cortex, to patients with striatal dysfunction: Parkinson's disease (n = 27), progressive supranuclear palsy (n = 20); to patients with prefrontal lesions (n = 10) and to normal control subjects (n = 24). The performance of each group was compared in four experiments: a delayed response task in which the correct answer was previously indicated by an explicit cue (externally guided task); delayed alternation and non-alternation tasks coupled with a delayed reversal task in which the patient had to discover the rule by himself in the absence of explicit cues (internally driven tasks). All groups of patients showed a short-term spatial representational memory deficit in the externally guided situation. Patients with striatal dysfunction showed difficulties in re-engaging attention on a new programme and in maintaining it. However, they did not express the spontaneous tendency to alternate nor the severe difficulties in disengaging from a previous pattern of response demonstrated by patients with prefrontal lesions. These results validate the concept of a striato-frontal functional system in humans and suggest the existence of two different levels of behavioural organization: elaboration of new programmes of behaviour in association with inhibition of previously established ones, that might be under frontal lobe control: maintenance of the new programme until the action has been accomplished and automatization for a routine utilization, that might be under control of the striatum.

Adaptation, Psychological↗