[Heidenhain's variant of Creutzfeldt-Jakob's disease]. / Forme de Heidenhain de la maladie de Creutzfeldt-Jacob.

INTRODUCTION: Creutzfeldt-Jakob's disease has various anatomoclinical presentations including a rare form with preponderant visual signs described by Heidenhain. In this form, the visual symptoms may be isolated for a few weeks, leading to multiple ophthalmological examinations. OBSERVATION: We report the case of a 75-year-old woman who developed isolated visual disorders which rapidly increased over a period of two months. Addition of neurological symptoms, abnormalities of EEG and positivity of 14-3-3 protein led to the diagnosis of Creutzfeldt-Jakob's disease. The patient died 14 months after the first neuroophthalmologic signs. The diagnosis was established by post-mortem examination and immuno-electrophoretic demonstration of type 1 prion protein. CONCLUSION: Heidenhain's form of Creutzfeldt-Jakob's disease highlights the importance of general rules for prevention of iatrogenic hazard during ophthalmological examinations.

Neuronal apoptosis in Creutzfeldt-Jakob disease.

Neuronal loss is a salient feature of prion diseases; however, its causes and mechanisms are unclear The possibility that it could occur through an apoptotic process has been postulated and is consistent with the lack of inflammation in prion disorders as supported by experimental studies. In order to test this hypothesis in humans, we examined samples of frontal and temporal cerebral cortex, striatum, thalamus, and cerebellum from 16 patients who died from Creutzfeldt-Jakob disease. They included 5 sporadic cases, 5 familial, 3 iatrogenic, and 3 cases with the new variant. These were compared with age and sex matched controls. Using in situ end labelling, we identified apoptotic neurons in all the cases of Creutzfeldt-Jakob disease. A single labelled neuron was found in the eldest control. Apoptotic neurons were mostly found in damaged regions and their presence and abundance seemed to correlate closely with neuronal loss. This supports the view that apoptosis of neurons is a feature of prion diseases and may contribute to the neuronal loss which is one of the main characteristics of these conditions. Neuronal apoptosis also correlated well with microglial activation, as demonstrated by the expression of major histocompatibility complex class II antigens, and axonal damage, as identified by beta-amyloid protein precursor immunostaining. In contrast, we found no obvious relationship between the topography and severity of neuronal apoptosis and the type, topography, and abundance of prion protein deposits as demonstrated by immunocytochemistry.

GnRH receptors in human granulosa cells: anatomical localization and characterization by autoradiographic study.

The presence of receptors for GnRH in human ovary has been investigated by quantitative autoradiography. Simultaneous visualization and characterization of specific receptors on frozen sections were obtained on six pairs of human ovaries. Among them only one exhibited a large preovulatory follicle. This dominant follicle exhibited a specific and high affinity binding capacity for 125I-GnRHa exclusively localized on the granulosa cell layer. Analysis of saturation curve indicates a Kd value of 0.22 nM and Bmax of 9.6 fmol/mg protein. In contrast LH-hCG binding sites were present in all antral follicles. These data demonstrate for the first time the presence of high affinity GnRH receptors in human granulosa cells at a late stage of follicular maturation.

Benzodiazepine binding sites and their modulators in hippocampus of violent suicide victims.

Benzodiazepine binding sites were studied by autoradiography in several hippocampic layers in brains of drug-free violent suicide victims (hanging) and matched controls. Kd was increased in suicides, and when brain sections from control subjects were incubated in the bath fluid that had previously served to incubate sections from suicides, Kd was increased in the same way. Results are discussed in terms of possible modulators of benzodiazepine binding sites, mainly tissue GABA and amino acid concentrations.

Alternative exon 3 splicing of the human major protein zero gene in white blood cells and peripheral nerve tissue.

The major protein zero (MPZ) is involved in peripheral myelin folding. Using nested reverse transcription-PCR, we amplified several fragments of MPZ mRNAs in white blood cells and in peripheral nerve tissue. Cloning of PCR products revealed the existence of three alternative splicing patterns: one resulted in the complete loss of exon 3 and two others induced partial skipping of the exon 3 sequence. All three alternative splicing mechanisms produced a frame-shift and created an identical premature stop codon in exon 4. We conclude that the existence of these MPZ RNA transcript variants may be the result of deliberate splicing decisions and may have functional implications in the cell.

Detection and cellular localization of enterovirus RNA sequences in spinal cord of patients with ALS.

OBJECTIVE: To investigate the possible association of persistent enterovirus (EV) infection with the development of ALS. BACKGROUND: Although ALS is a clinically well-defined motor neuron disease, little is known about the etiology and pathogenesis of the sporadic cases. Among the different causes that have been hypothesized, conflicting results have been reported about the possible role of persistent enteroviral infection. METHODS: Reverse transcriptase-PCR (RT-PCR) and direct RT in situ PCR (RT-IS-PCR) were performed in formaldehyde-fixed spinal cord samples of 17 patients with confirmed ALS and 29 control subjects with no history of motor neuron disease. When obtained, PCR products were sequenced subsequently. RESULTS: Using direct RT-IS-PCR, EV nucleic acid sequences were detected in 15 (88.3%) of 17 patients with ALS compared to 1 (3.4%) of 29 control subjects. PCR products were located in neuronal cell bodies of the anterior horns of the spinal cord. The RT-PCR products obtained in 13 of the 17 patients with ALS showed between 94% and 86% homology with echovirus 7 sequences. CONCLUSION: The 88.3% rate of detection of enterovirus (EV) nucleic acids in the neuronal cell bodies within the gray matter of the spinal cord of patients with ALS strongly suggests association between persistent EV RNA and ALS. Further work is required to confirm that the persisting EV sequences we detected are somehow involved in the development of ALS.

Neuropathologic variants of sporadic Creutzfeldt-Jakob disease and codon 129 of PrP gene.

OBJECTIVES: To determine the contribution of methionine/valine (Met/Val) polymorphism at codon 129 of the prion protein (PrP) gene in the neuropathologic pattern and mechanisms of lesion development in sporadic Creutzfeldt-Jakob disease. BACKGROUND: Creutzfeldt-Jakob disease is a transmissible spongiform encephalopathy characterized by a conformational change of PrP and a variety of PrP deposits in the brain, some of which aggregate into amyloid plaques. METHODS: The authors semiquantitatively assessed neuropathologic lesions and performed PrP immunolabeling in 70 patients (39 Met/Met, 11 Met/Val, 20 Val/Val) who had died in France between 1994 and 1998. RESULTS: Met/Met cases (mild lesions mostly involving the occipital areas, low PrP load, few focal PrP nonamyloid deposits, no amyloid plaques) contrasted with Met/Val cases (marked lesions especially in the parahippocampal gyrus, high PrP load, numerous amyloid plaques) and with Val/Val cases (younger patients, longer course of disease: 11.5 +/- 3 months, and distinct neuropathology: severe lesions heavily involving the hippocampal formation and basal ganglia, high PrP load, numerous focal nonamyloid deposits, rare amyloid plaques). The course of Val/Val patients younger than age 55 was particularly long (19.9 +/- 7 months), and the isocortex bore the brunt of the pathology, suggesting a distinct variety. CONCLUSIONS: Polymorphism at codon 129 modulates the phenotype of sporadic Creutzfeldt-Jakob disease. The Val genotype enhances the production of proteinase-resistant PrP, and the Met/Val genotype facilitates its aggregation into amyloid plaques.

Dementia with Lewy bodies in a neuropathologic series of suspected Creutzfeldt-Jakob disease.

Discriminating Creutzfeldt-Jakob disease (CJD) from dementia with Lewy bodies (DLB) may be clinically difficult to achieve. The authors describe 10 patients with DLB initially referred to the French Network of Human Spongiform Encephalopathies as having suspected CJD. In a series of 465 autopsied cases, DLB ranked second among degenerative alternative diagnoses to CJD. The authors analyzed the factors that contributed to misleading the diagnosis, and suggest that the detection of 14-3-3 protein in CSF may be useful to distinguish CJD from DLB.

Substance P- and enkephalin-immunoreactive neurons in the hippocampus and related areas of the human infant brain.

Neurons strongly immunoreactive for substance P are present as subpopulations in the stratum oriens, pyramidal layer and polymorphic layer of the hippocampus of the human infant. Substance P immunoreactive terminals are numerous on other neuronal cell bodies in the polymorphic layer and over pyramidal cells of the subiculum and the CA1, 2 and 3 regions. There is a high density of substance P-immunoreactive axons in the granular layer. Enkephalin immunoreactive neurons are relatively few in number and are present in the polymorphic and pyramidal layers. The results indicate that substance P probably plays a major role in short range circuits in the human hippocampus and that intrinsic enkephalin neurons probably play a relatively minor role.

Anatomical distribution of somatostatin immunoreactivity in the infant brainstem.

The distribution of somatostatin-immunoreactive structures in the infant brainstem was investigated using the peroxidase-antiperoxidase technique. A wide distribution of somatostatin-immunoreactive cell bodies and fibers was observed throughout the brainstem. Numerous somatostatin-immunoreactive cell bodies and fibers were present in several areas of the brainstem including the substantia grisea centralis and the reticular formation. Some immunoreactive cell bodies were seen in cranial nerve nuclei such as the nucleus praepositus, the nucleus nervi hypoglossi and the vestibular nuclei. Immunoreactive fibers were seen in the nucleus cuneatus, the locus coeruleus, the nucleus tractus solitarius, the nucleus ambiguus, the nucleus tractus spinalis nervi trigemini and the dorsal horn of the spinal cord. These data were in agreement with previous works on the human adult. However, a high density of somatostatin-immunoreactive cell bodies and fibers in the interpeduncular nucleus and in the nucleus centralis superior, and a dense network of somatostatin-immunoreactive fibers in the dorsal part of the nucleus inferior olivarius, were also observed. The role of somatostatin in some brainstem nuclei and its probable implication in some specific neuropathological diseases of the infant brainstem is discussed.

Regional distribution of somatostatin binding sites in the human hypothalamus: a quantitative autoradiographic study.

Using in vitro quantitative autoradiography and [125I]Tyr0-D-Trp8SRIF 14 as radioligand, we characterized the detailed distribution of somatostatin binding sites in human hypothalamus of both infants and adults. Guanosine triphosphate pretreatment, before incubation, allowed us to detect higher [125I]Tyr0-D-Trp8SRIF 14 binding site densities in hypothalamic structures such as preoptic and anterior hypothalamic areas and ventromedial and dorsomedial nuclei. In contrast, guanosine triphosphate was without effect in the other hypothalamic regions. The regional effects of guanosine triphosphate pretreatment were not different in infant and adult hypothalamus. Scatchard analysis showed that in a guanosine triphosphate-sensitive region (preoptic area) and a guanosine triphosphate-insensitive area (infundibular nucleus), [125I]Tyr0-D-Trp8SRIF 14 bound to a single class of binding sites. Affinities were similar in both regions, not modified by guanosine triphosphate pretreatment and not different in the adult (1.5 +/- 1.2 nM vs 3.2 +/- 2.1 nM for preoptic area and infundibular nucleus, respectively) and infant (0.9 +/- 0.5 nM vs 2.4 +/- 1.7 nM for preoptic area and infundibular nucleus). [125I]Tyr0-D-Trp8SRIF 14 binding sites were widely distributed in the anterior, mediobasal and posterior hypothalamus. Somatostatin 28 was twice as potent as somatostatin 14 to displace [125I]Tyr0-D-Trp8SRIF 14 binding in the preoptic area and infundibular nucleus. However, IC50s were 30 times lower in the preoptic area as compared with the infundibular nucleus. In adult as well as in infant, high densities were found mainly in the diagonal band of Broca, preoptic area and infundibular nucleus. Intermediate densities were localized in the anterior hypothalamic area, ventromedial, dorsomedial and lateral mammillary nuclei. The dorsal hypothalamic area, the paraventricular and medial mammillary nuclei displayed low but measurable densities. The only marked difference in the distribution of [125I]Tyr0-D-Trp8SRIF 14 binding sites in adult vs infant was observed in the medial and tuberal nuclei where the concentrations were seven-fold higher in adult hypothalamus.

Ontogeny of peptides in human hypothalamus in relation to sudden infant death syndrome (SIDS).

The brains of mammals are not mature at birth, in particular in humans. Growth and brain development are influenced by the hormonal state in which the hypothalamus plays the major regulatory role. The maturation of the hormonal patterns leads to the physiological establishment of chronological variations as revealed by the circadian variations of both hypothalamic peptides and pituitary hormones (as illustrated for hypothalamic-pituitary-thyroid axis by the determination of thyro-stimulating hormone (TSH) and thyrotropin-releasing hormone (TRH) circadian rhythms in the rat (Jordan et al., 1989)). It has been established that hypothalamic peptide variations are regulated by hormonal feed-back and amine systems, with the maturation of the latter also being dependent upon the whole functional maturation of the brain. Though these systems have been studied in the rat, very little information is currently available with regard to the human brain. The only biochemical or immunohistochemical information published to date concerns either the fetus or the adult. We have studied four main peptidergic systems (somatostatin-releasing inhibiting factor (SRIF), thyrotropin-releasing hormone (TRH), luteinizing hormone-releasing hormone (LHRH) and delta sleep inducing peptide (DSIP) in post-mortem adults and infants and in sudden infant death syndrome (SIDS) brains either by autoradiography and/or immunochemistry of radioimmunology. From a technical point of view, human brain studies display certain pitfalls not present in animal studies. These may be divided into two subclasses: ante- and post-mortem. Ante-mortem problems concern mainly sex, laterality, nutritional and treatment patterns while post-mortem problems concern post-mortem delay and conditions before autopsy and hypothalamic dissection. This might induce dramatic changes in morphological, immunochemical and autoradiographic evaluations. The matching of pathological subjects with controls is particularly difficult in the case of SIDS because of the rapid changes which take place in physiological regulatory processes during the first year of life. Thus, the treatment of hypothalamic tissue samples both for immunochemistry, radioimmunology and autoradiographic studies required techniques which must be rigorously controlled. For example, SRIF studies were carried out with three different antibodies, which gave similar results. The use of different technical procedures as well as different antibodies is discussed. These types of differences might explain, at least in part, the discrepancy observed until now. As previously described in the fetus (Bugnon et al., 1977b; Bouras et al., 1987), we confirmed that in the infant hypothalamic SRIF immunoreactive cell bodies are present in the paraventricular and suprachiasmatic nuclei and in the periventricular area.(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence for multiple opioid receptors in the human posterior pituitary.

The distribution and quantification of opioid receptor types in post-mortem human pituitary cryostat sections was determined by quantitative in vitro receptor autoradiography. Highly specific radioligands were used for each opioid receptor type i.e. [125l]-FK-33-824 for mu-opioid sites, [125l][D.Ala2]-Deltorphin-l for delta-opioid sites and 3H-U69,593 for kappa-opioid sites. None of the five specimens tested exhibited any labeling in the anterior lobe of the pituitary for the three radioligands. As for the posterior pituitary, all 5 specimens contained both mu and kappa-opioid binding sites whereas none of them showed delta-binding sites. The presence of both mu- and kappa-opioid binding sites in the human posterior pituitary contrasts with previous findings in the rat where only kappa-sites have been found. The present study could contribute to understanding of the functional action of opioids in the human pituitary.

Beta-endorphin: regional levels profile in the brain of the human infant.

Immunoradiometrical determinations of beta-endorphin (beta-EP) levels in 29 discrete brain regions from a series of victims of "Sudden Infant Death Syndrome" yielded a uniformly low levels profile in various areas of telencephalon, thalamus, pons, cerebellum and medulla oblongata. This low levels profile was interrupted by intermediate and high beta-EP levels in the midbrain and in two diencephalic zones. This study provides, for the first time, a comprehensive, neurochemically determined regional profile of beta-EP levels in the brain of the human infant.

Quantitative autoradiographic study of somatostatin and neurotensin binding sites in medulla oblongata of SIDS.

Quantitative autoradiography analysis of neurotensin (NT) and somatostatin (SS) binding sites was performed on coronal sections of the medulla oblongata from 2 fetuses, 6 controls and 7 victims of Sudden Infant Death Syndrome (SIDS). Throughout the first postnatal year, mean SS binding site density was similar in controls and SIDS in all structures of the medulla oblongata. The density of neurotensin binding sites was significantly higher in the nucleus of tractus solitarius (NTS) of SIDS than in controls, but there was no significant differences in the other areas of the medulla oblongata. Our findings suggest an immature developmental pattern of increased NT binding sites the NTS of SIDS. This alteration may be related to an abnormal central cardiorespiratory and arousal control which is thought to be present in SIDS.

Evaluation of endozepine-like immunoreactivity in the frontal cortex of suicide victims.

Diazepam-binding inhibitor (DBI) and its processing products, including the octadecaneuropeptide (ODN), are polypeptides called endozepines which have multiple biological effects, including regulation of mitochondrial steroidogenesis and modulation of GABA-gated chloride channels. Concentrations of ODN-like immunoreactivity (ODN-Li) were measured by radioimmunoassay in the frontal cortex of nine drug-free suicides and nine drug-free sudden-death victims. The level of ODN-Li was higher in the right than in the left frontal cortex, in both suicide (p < 0.05) and control (p < 0.02) subjects. No significant differences were found between suicides and controls either in the right and left cortex, or when considering the gender and the post-mortem diagnosis of depression.

Neurotensin immunoreactive neurons in the human infant diencephalon.

Neurotensin-like immunoreactive (NT-IR) neurons are present in discrete subregions of the anterior, medial and lateral thalamic nuclear groups of the human infant brain. The pulvinar is notably rich in such cells. Smaller numbers of cells are present in the ventral group, centromedian nucleus, reticular nuclei and intralaminar nuclei. Neurotensin immunoreactive axons accumulate dorsally in the thalamus and cross the deep white matter. The cerebral cortex contains a rich network of NT-IR axons. The subthalamic nucleus is rich in NT-IR neurons. Within the hypothalamus NT-IR perikarya are present in parts of the lateral and tuberal regions and in the lateral mammillary area. NT-IR axons are widespread being particularly prominent in parts of the tuberal region and the mammillary body.

Neurotensin immunoreactive structures in the human infant striatum, septum, amygdala and cerebral cortex.

Neurotensin immunoreactive (NT-IR) neuronal perikarya are present in small numbers in the bed nucleus of the stria terminalis, lateral olfactory stria, substantia innominata, caudate nucleus and putamen of the human infant forebrain. Larger numbers of perikarya are present in the amygdala and related structures. NT-IR axons are present in the medial septal area, bed nucleus of the stria terminalis, caudate nucleus, putamen and amygdala. The cerebral cortex contains a rich network of NT axons with an accentuation in layer II. This network appears to be derived from bundles of axons which traverse the deep white matter from the thalamus.

Quantitative autoradiography of 5-HT1D and 5-HT1E binding sites labelled by [3H]5-HT, in frontal cortex and the hippocampal region of the human brain.

In human cortex and hippocampus area, [3H]5-HT (5 nM) labels 5-HT1A, 5-HT1D and 5-HT1E sites. After masking 5-HT1A receptors by 0.1 microM 8-OH-DPAT, the binding displaced by 0.1 microM 5-CT presumably represented 5-HT1D sites and the remaining binding 5-HT1E sites. In frontal cortex, 5-HT1A receptors represented the main binding in layers II and VI and a lower fraction in other layers. 5-HT1D and 5-HT1E sites, were more homogeneously distributed in layers II to VI (21-34% of specific [3H]5-HT binding). 5-HT1E sites were of similar affinities (KD close to 6-8 nM) in the cortical layers II to VI. In CA1 field of hippocampus, (pyramidal layer, stratum radiatum, molecular layer), CA2 and dentate gyrus, 5-HT1A receptors represented the major fraction, 5-HT1D sites a significant fraction and 5-HT1E a minor fraction of the specific [3H]5-HT binding. In CA3-CA4 fields, 5-HT1A receptors were less densely present, 5-HT1D sites were predominant and 5-HT1E sites represented a significant fraction (27%). The highest densities of 5-HT1E sites have been measured in subiculum, where 5-HT1A, 5-HT1D and 5-HT1E binding sites were equally represented and in entorhinal cortex where 5-HT1E sites represented the major binding in layer III. They were also present in layers II and IV (29 and 24%) and, to a lesser extent, in layers V and VI. 5-HT1A sites were predominant in layer VI, II and V and were less abundant in other layers. 5-HT1D were homogeneously present in layers II, III, IV and were present in low amounts in other layers. No 5-HT1E were detected in choroid plexus, where [3H]5-HT was dramatically reduced by mesulergine (5-HT2C receptors). No significant displacement of [3H]5-HT by mesulergine was measured in other structures.

Neurotensin immunoreactivity in the human cingulate gyrus, hippocampal subiculum and mammillary bodies. Its potential role in memory processing.

Neurotensin immunoreactive neurons comprise the majority of large perikarya in the human subiculum and project axons to the alveus, fimbria, fornix and neuropil of the mammillary bodies. These regions are prominently involved in conditions such as Wernicke's and Alzheimer's disease in which memory is impaired. Neurotensin has potential significance as a peptide in a human brain circuit which may serve a role in memory processing.