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P Hantraye

Publications and source records attributed to P Hantraye.

At least 55 records · Page 3Linked to original sources
PubMed1995

Clinical correlates of [18F]fluorodopa uptake in five grafted parkinsonian patients.

To assess the efficacy of fetal mesencephalic grafts in Parkinson's disease, it is important to know if the grafted cells survive and are functional. Positron emission tomography (PET) and [18F]fluorodopa ([18F]dopa) have been used to demonstrate the survival of the grafted cells, but the relationship of [18F]dopa uptake changes in the grafted striatum to motor function remains unclear. We investigated this question with 16 serial PET scans in 5 severe parkinsonian patients unilaterally grafted in whom we found a significant and progressive increase of the [18F]dopa uptake in the grafted putamen. The number of patients was too small to assess the sensitivity of [18F]dopa PET scans in individual patients. Yet, by analyzing the 16 serial PET scans we found a correlation between the [18F]dopa uptake (Ki) in the grafted putamen and the percentage of daily time spent "on," suggesting that Ki changes have a functional meaning. In addition, the Ki values were correlated with the contralateral finger dexterity to the same extent in both the grafted and nongrafted putamen. These results indicate that [18F]dopa uptake reflects the motor function of the opposite side of the body, similarly in the grafted and ungrafted putamen, at least in terms of these tasks. Finally, extrapolating from these correlations offers the suggestion that clinical optimal results of the graft could be achieved if the graft brings the Ki values in the putamen to about two standard deviations of mean control values.

Brain↗
PubMed1995

Rationale for intrastriatal grafting of striatal neuroblasts in patients with Huntington's disease.

Huntington's disease is a genetic disease, autosomal and dominant, that induces motor disorders, an inexorable deterioration of higher brain functions and psychiatric disturbances. At present, there are no known therapeutics against Huntington's disease. The Network of European CNS Transplantation and Restoration (NECTAR) has begun a program aimed at defining the conditions under which intrastriatal transplantation of fetal striatal cells could be attempted as an experimental treatment for Huntington's disease. This review presents the reasons why our group is considering participating in these trials. The validity of this therapeutic approach is supported by three main series of data: (i) neuropathological, clinical and imaging data indicate that Huntington's disease is, above all, a localized affection of a specific neuronal population ("medium-spiny" neurons) in the striatum; (ii) a large body of experimental results, obtained in rats and non-human primates, demonstrates that transplanted fetal striatal cells are able to integrate the host brain and to substitute for previously lesioned host striatal neurons; (iii) expertise in clinical neural transplantation has now been acquired from the treatment of patients with Parkinson's disease. These different sets of data are presented and discussed in this review. There are a number of problems which do not yet appear to be entirely resolved, nor are they likely to be using the experimental models currently available. These problems are identified and explicitly presented as working hypotheses. (1) Anatomo-functional results obtained in rodents and non-human primates with excitotoxic striatal lesions can serve as a basis for the extrapolation of what can be obtained from patients with Huntington's disease. (2). Huntington's disease can be efficiently fought by substituting degenerated striatal neurons alone. (3) Huntington's disease is due to a genetic defect which either hits the neurons that carry it directly or hits them indirectly only after several decades. Transplanted neurons, because they do not carry the gene or because they are of fetal origin, will not be rapidly affected by the ongoing disease process. Given the current state of knowledge, intracerebral transplantation appears to be the most serious opportunity (if not the only one that has been experimentally validated) for clinical improvement to be obtained in patients with Huntington's disease. The purpose of this review is to open a scientific discussion on its experimental bases before actual clinical trials start.

Animals↗
PubMed1995

Downregulation of amyloid precursor protein inhibits neurite outgrowth in vitro.

The amyloid precursor protein (APP) is a transmembrane protein expressed in several cell types. In the nervous system, APP is expressed by glial and neuronal cells, and several lines of evidence suggest that it plays a role in normal and pathological phenomena. To address the question of the actual function of APP in normal developing neurons, we undertook a study aimed at blocking APP expression using antisense oligonucleotides. Oligonucleotide internalization was achieved by linking them to a vector peptide that translocates through biological membranes. This original technique, which is very efficient and gives direct access to the cell cytosol and nucleus, allowed us to work with extracellular oligonucleotide concentrations between 40 and 200 nM. Internalization of antisense oligonucleotides overlapping the origin of translation resulted in a marked but transient decrease in APP neosynthesis that was not observed with the vector peptide alone, or with sense oligonucleotides. Although transient, the decrease in APP neosynthesis was sufficient to provoke a distinct decrease in axon and dendrite outgrowth by embryonic cortical neurons developing in vitro. The latter decrease was not accompanied by changes in the spreading of the cell bodies. A single exposure to coupled antisense oligonucleotides at the onset of the culture was sufficient to produce significant morphological effects 6, 18, and 24 h later, but by 42 h, there were no remaining significant morphologic changes. This report thus demonstrates that amyloid precursor protein plays an important function in the morphological differentiation of cortical neurons in primary culture.

Amyloid↗
PubMed1995

Effects of chronic MPTP and 3-nitropropionic acid in nonhuman primates.

Compelling evidence suggests that a defect in energy metabolism may play a role in the pathogenesis of various degenerative disorders including Parkinson's disease and Huntington's disease. The behavioural and neuropathological consequences in primates of chronic systemic administration of mitochondrial toxins which impair oxidative metabolism are of considerable interest. In the past few years observations have been published describing the behavioural, biochemical and histological consequences of chronic low-dose systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 3-nitropropionic acid in baboons. The results of these studies strongly support the view that chronic energy metabolism impairment is involved in the pathogenesis of Parkinson's and Huntington's diseases.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

TH mRNA over-expression in rats with chronic excitotoxic striatal lesions.

Twenty weeks after ibotenic acid lesions of the striatum, the amount of tyrosine hydroxylase (TH) in this structure was markedly increased. This was accompanied by a 3-fold increase in TH mRNA levels in the ipsilateral subtantia nigra (SN). Striatal levels of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) were markedly reduced. In the nucleus accumbens, spared by the lesion, DA neurotransmission was also altered, as evidenced by a reduction of DA and DOPAC, but no increase in TH could be detected. TH mRNA levels were moderately enhanced in the ventral tegmental area (VTA). Thus, lesioning in the striatum induces TH gene activation in both SN and VTA neurones, not strictly related to DA function at the terminal level.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

PET- and MRI-based assessment of glucose utilization, dopamine receptor binding, and hemodynamic changes after lesions to the caudate-putamen in primates.

In vivo physiological changes associated with striatal pathology were determined by measurement of glucose utilization, binding to D1 receptors and dopamine reuptake sites, regional blood flow, and behavior before and after unilateral quinolinate infusions into caudate-putamen in three nonhuman primates (Macaca fascicularis and Macaca mulatta). Following the quinolinate lesion, symptoms similar to those of Huntington's disease could be induced by dopamine agonist treatment. In addition, all animals showed a long-term decrease in glucose utilization in the caudate by [19F]fluoro-2-deoxy-D-glucose positron emission tomography (PET). At 4-6 weeks following the lesion the average decrease in glucose utilization in the caudate-putamen was between 40 and 50% of the prelesion values in primates with large lesions. Corresponding caudate-putamen regional blood volume in these animals showed a 61 and 74% decrease as studied by magnetic resonance imaging with somewhat smaller changes observed in an index of cerebral blood flow. The caudate-putamen uptake rate constants for D1 receptors reflected neuronal loss and decreased by an average 40 and 48%, as determined by 11C-labeled Schering compound (SCH 39 166) and PET. Dopamine reuptake sites and fibers assessed by the 11C-labeled cocaine analog, WIN 35 428 compound, and PET showed a temporary decrease in areas with mild neuronal loss and a long-term decrease in striatal regions with severe destruction. These results, which were consistent with behavioral changes and neuropathology seen at postmortem examination, can be related to in vivo physiological studies of Huntington's disease patients.

Acetylcholinesterase↗
PubMed1994

Dopamine terminal loss and onset of motor symptoms in MPTP-treated monkeys: a positron emission tomography study with 11C-CFT.

We studied the time course of dopamine (DA) terminal loss in three macaca fascicularis injected with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) intravenously every 10-14 days for up to 389 days. Striatal DA terminal loss was monitored in vivo by positron emission tomography using 11C-CFT (WIN 35,428), a cocaine derivative that labels the DA transporter. The 11C-CFT uptake rate constant in the striatum of MPTP-treated monkeys decreased exponentially over time, with the putamen significantly more affected than the caudate. Spontaneous locomotor activity decreased in parallel with the decline of the 11C-CFT uptake rate; however, overt parkinsonian signs appeared only after the 11C-CFT uptake rate had declined to about 30% of the pretreatment values. We conclude that a long-term intermittent mode of administration of MPTP can lead to a pattern of terminal loss that closely resembles idiopathic Parkinson disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Chronic MPTP treatment reproduces in baboons the differential vulnerability of mesencephalic dopaminergic neurons observed in Parkinson's disease.

Chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to baboons was shown previously to result in a motor syndrome and a pattern of striatal dopaminergic fibre loss similar to those observed in idiopathic Parkinson's disease. In the present study, tyrosine hydroxylase-immunoreactive neurons were quantified in the mesencephalon of control (n = 4) and chronically MPTP-treated (n = 3) baboons. MPTP induced a significant reduction in neuronal cell density in the substantia nigra (63.8% reduction) and the ventral tegmental area (53.1%). Within the substantia nigra, obvious mediolateral and dorsoventral gradients of neuronal cell loss were observed. First, the pars lateralis was more affected than the lateral divisions of the pars compacta (89.6% vs 73.8% cell loss), which in turn were more depleted than the medial divisions (60.1% reduction). Second, the ventral regions of the pars compacta were more degenerated than the dorsal parts (82.4 vs 51.5% decrease). This regional pattern is strikingly similar to that observed in Parkinson's disease and indicates that two subpopulations of dopaminergic neurons are distinguishable on the basis of their differential vulnerability to MPTP. Finally, the present study confirms that chronic mitochondrial complex I inhibition using MPTP in primates is sufficient to reproduce the typical dopaminergic cell loss and striatal fibre depletion observed in Parkinson's disease.

Animals↗
PubMed1994

Bilateral motor improvement and alteration of L-dopa effect in two patients with Parkinson's disease following intrastriatal transplantation of foetal ventral mesencephalon.

Several recent reports have suggested that foetal ventral mesencephalic transplants could alleviate motor symptoms in patients with Parkinson's disease. Expectations of future success must be clarified by precise analysis of the extent and limitation of recovery associated with an assessment of function of the graft using [18F]fluorodopa (18F-dopa) PET. Two patients with idiopathic Parkinson's disease, severely impaired despite optimal medication, have been followed 10 and 17 months after stereotaxic unilateral intrastriatal transplantation of neural cells dissociated from human foetal ventral mesencephalon. Analysis of the clinical evolution complied with the protocol established in the 'Core Assessment Program for Intracerebral Transplantation'. Both patients have benefited from the transplantation in their daily activities and in motor timed tests, although they still exhibit parkinsonian symptoms and require L-dopa therapy. This is associated with a gradual increase in 18F-dopa uptake at the site of grafting. There are two major clinical changes: (i) a bilateral motor improvement for the speed of movements (the quality of movements improved almost exclusively on the side contralateral to the graft); (ii) a change in the outcome of the L-dopa treatment as exemplified by a postoperative transient period of heavy dyskinesias and subsequent additive actions of the two treatments. These results confirm that neural transplantation may be useful for patients with Parkinson's disease. The improvement recorded on the side ipsilateral to the graft does not match that observed on the contralateral side and it is proposed that bilateral transplantation may be necessary. The existence of a transient postoperative period of heavy dyskinesias suggests that the patients may benefit from a controlled decrease of L-dopa intake after grafting.

Adult↗
PubMed1993

Stable parkinsonian syndrome and uneven loss of striatal dopamine fibres following chronic MPTP administration in baboons.

The progressive degeneration of dopamine neurons observed in idiopathic Parkinson's disease was mimicked by injecting low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to baboons, on a chronic basis. Five Papio papio baboons were treated on two different regimens (chronic intravenous administration at weekly intervals for 20-21 months or, daily MPTP treatment for five days followed five to six months later by chronic weekly injections for 5-21.5 months). All animals were assessed for motor symptoms during and after neurotoxic treatment. Both regimens invariably resulted in the appearance of a progressive and irreversible syndrome characterized by action and resting tremor, cogwheel rigidity, postural impairments, hypokinesia and bradykinesia. In some animals, symptoms of resting tremor and rigidity initially restricted to one side of the body became bilateral within a few months of treatment. Subtle abnormalities that may be found in idiopathic Parkinson's disease such as alterations of the blink reflex response were also noted. Neuropathological examination of caudate nucleus, putamen, substantia nigra and ventral tegmental area in brain sections stained for tyrosine hydroxylase showed a typical uneven striatal dopamine fibre loss and a neuronal depletion in the dopaminergic mesencephalic cell groups that reproduce those observed in idiopathic Parkinson's disease. Immunocytochemical observations and behavioural data show that chronic rather than acute MPTP injection regimens can replicate most of the neuropathological and the clinical features typical of idiopathic Parkinson's disease, possibly by increasing the ability of this neurotoxin to target specific subpopulations of mesencephalic dopaminergic neurons.

Animals↗
PubMed1993

Synthesis of 3-[18F]fluoromethyl-BTCP and evaluation as a potential PET radioligand for the dopamine transporter in baboons.

In an attempt to visualize in vivo the dopamine transporter and evaluate its potential as an imaging tool for monitoring dopamine fiber degeneration by positron emission tomography, the 18F-positron-emitting analogue of 3-fluoromethyl-1-[1-(2-benzothienyl)-cyclohexyl]-piperidine, [18F]BTCP, was synthesized and tested in a primate model of hemiparkinsonism. [18F]BTCP was obtained from cyclotron-produced n.c.a. [18F]fluoride (110 min half-life) and by nucleophilic substitution from 3-bromomethyl-BTCP with a radiochemical yield of 6% (decay-corrected). After intravenous injection, the cerebral distribution of the radioactivity was observed mainly in cortical areas and cerebral structures enriched in catecholamine reuptake sites such as the caudate-putamen complex and the thalamus. The binding ratio, defined with respect to the cerebellum (taken as a region of non-specific binding), was highest in the thalamus (1.42), intermediate in the putamen (1.36) and lowest in the caudate nucleus (1.17), suggesting that some specific binding occurs in these regions. After saturation of dopamine and norepinephrine transporters by nomifensine, the binding ratio in the thalamus, putamen and caudate nucleus striatum remained essentially unchanged in the non-lesioned hemisphere. When comparing binding ratios between the intact and the dopamine-denervated striatum, there was a modest loss of binding in the denervated striatum, suggesting that degeneration of dopaminergic fibers could be detected using 3-[18F]fluoromethyl-BTCP. However due to a high non-specific binding in vivo, the interest of 3-[18F]fluoromethyl-BTCP to image the dopamine reuptake system in vivo appears rather limited.

Animals↗
PubMed1992

Intrastriatal transplantation of cross-species fetal striatal cells reduces abnormal movements in a primate model of Huntington disease.

Huntington disease is a neurological movement disorder involving massive neuronal death in the caudate-putamen region of the brain. Neither preventive nor curative therapy exists for this disease. The implantation of cross-species striatal neural precursor cells into the lesioned striatum of nonhuman primates (baboons) reduced the abnormal movements seen in the disease model. These abnormal movements reappeared after immunological rejection of the implanted striatal cells and were not modified by transplantation with nonstriatal cells. These findings encourage further experimentation toward the use of cell sources other than human fetal cells in a potential clinical application to Huntington disease.

Animals↗
PubMed1992

Carbon 13 NMR study of glycogen metabolism in the baboon liver in vivo.

In vivo glycogen metabolism was investigated at 2 Tesla by 13C NMR in the baboon liver. Two concentric surface coils were used for 13C observation and proton decoupling, respectively. Spectra were acquired in 2 to 10 minutes with a 60 ms repetition time. After 3 hours of glucose infusion in the 48 hr fasted animal, 3 g of 99%-enriched [1-13C]glucose were injected. The distribution of the label on C-1 and also C-2, C-5 and C-6 of glycogen indicated 65% and 35% contributions of the direct and indirect pathways to glycogen synthesis from glucose, respectively. The results show that hepatic metabolic pathways and rates can be followed in vivo in large animals by 13C NMR at 2 Tesla.

Animals↗
PubMed1992

Magnetic resonance imaging to monitor pathology of caudate-putamen after excitotoxin-induced neuronal loss in the nonhuman primate brain.

We used MR imaging to locate and monitor in vivo the pathological events taking place 2 to 4 weeks after unilateral striatal injections of ibotenic acid (IA) in the Papio papio baboon. As early as 2 weeks after IA injections, excitotoxic lesions in the caudate and the putamen were directly visualized on T1-weighted images as small areas of low signal intensity. On T2-weighted images, the lesion sites were visualized as areas of high-intensity signal, spreading over larger areas than the corresponding regions in T1-weighted images. These alterations of T2-values in the lesioned striatum persisted 4 weeks after surgery. However, as the striatal degeneration progressed from 2 to 4 weeks after lesion, the size of the areas of high signal intensity on T2-weighted images decreased, whereas the same regions appeared essentially unmodified on T1-weighted images. A marked enlargement of the ipsilateral lateral ventricle (a characteristic of excitotoxic striatal lesions) could be detected 4 weeks after surgery, on both axial T1- and T2-weighted images. Comparisons of MR images with postmortem anatomical data indicated that areas of increased T1 values corresponded to regions of severe neuronal depletion (a direct result of the excitotoxic lesion), whereas areas of increased T2 values corresponded to regions of increased content in astrocytes and ferritin and probably in the early period following lesion (2 weeks) to a superimposed edema.

Animals↗
PubMed1992

6-[18F]fluoro-L-dopa uptake and [76Br]bromolisuride binding in the excitotoxically lesioned caudate-putamen of nonhuman primates studied using positron emission tomography.

The functional status of the dopaminergic system following striatal excitotoxic lesions was studied in living baboons by positron emission tomography (PET) using 6-[18F]fluoro-L-dopa as specific tracer for the presynaptic dopaminergic terminals and [76Br]bromolisuride as selective dopamine D2-receptor marker. The glutamate receptor agonist ibotenic acid (IA) was injected into the right caudate-putamen of six baboons to induce a neuropathological and behavioral model of Huntington's disease (HD). In vivo PET studies performed 3 to 6 months after the IA injections showed that subtotal excitotoxic lesions of the CP were accompanied by changes in the kinetic of [76Br]bromolisuride binding indicating a dose-dependent reduction in binding sites in the lesioned striatum of all IA-injected animals. In the most severely lesioned animals, there was also a decrease in the uptake of the nigrostriatal dopaminergic marker. The loss of D2-receptors and decrease in striatal dopamine uptake are consistent with clinical and postmortem findings in HD. In addition, the decrease in 6-[18F]fluoro-L-dopa uptake confirms previous studies performed in a rat model of HD suggesting a continuous decline of nigral dopamine cell function following destruction of their intrinsic striatal target neurons. The results of our experience to date in PET studies of 6-[18F]fluoro-L-dopa and [76Br]bromolisuride binding in IA-lesioned primates indicate that PET can identify effects of cell loss on markers of pre- and postsynaptic function in the striatum of living subjects.

Animals↗
PubMed1992

Synthesis, tissue distribution in rats and PET studies in baboon brain of no-carrier-added [18F]RU 52461: in vivo evaluation as a brain glucocorticoid receptor radioligand.

11,17 beta-Dihydroxy-6-methyl-17 alpha-(3-[18F]fluoro-prop-1- ynyl)androsta-1,4,6-trien-3-one [( 18F]RU 52461), an 18F-analog of RU 28362, was synthesized by bromide displacement with [18F]fluoride in 12-30% overall radiochemical yield (decay-corrected) within 140 min from end of bombardment (EOB). The specific activity was 900-1500 mCi/mumol (33.3-55.5 GBq/mumol) at the end of synthesis (EOS). Biodistribution studies indicated high adrenal and pituitary retention, and uniformly low uptake of [18F]RU 52461 in all other brain regions of the rat. Except for the pituitary, no specific receptor-mediated uptake of [18F]RU 52461 could be demonstrated using saturating doses of unlabeled RU 52461 in rat brain. While no change was observed throughout the brain areas in adrenalectomized rats and in animals coinjected with dexamethasone, when compared to controls. PET studies revealed extremely low levels of radioactivity in baboon brain. Therefore, [18F]RU 52461 does not appear to cross the blood-brain barrier, suggesting that this radiopharmaceutical is not suitable to visualize the brain glucocorticoid binding sites by PET.

Androstatrienes↗
PubMed1992

Dopamine fiber detection by [11C]-CFT and PET in a primate model of parkinsonism.

Monkeys were treated on two regimens of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injections to achieve dopamine fiber degeneration of differing severities. A rapid treatment regimen produced a severe parkinsonian syndrome, whereas an intermittent regimen did not cause locomotor symptoms to appear up to 25 weeks. High resolution PET scanning of dopamine nerve terminals revealed that the specific binding of the dopamine transporter [11C]-WIN 35,428 ([11C]-CFT) was diminished by 94% (caudate nucleus) and by 93% (putamen) in the symptomatic monkey. Decreases of 65 and 67% were detected in these regions in the non-symptomatic monkey. Post-mortem immunocytochemical evaluation of presumed dopamine fibers by tyrosine-hydroxylase showed similar reductions in the symptomatic animal.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗