[Familial orthochromatic leukodystrophy: clinicopathological study of two cases]. / Leucodystrophies orthochromatiques familiales.

This paper reports the clinico-pathological data in a French family with orthochromatic leukodystrophy. The parents were first cousins and had seven children. Among those, two sisters and one brother presented with neurological signs, with onset around the 5(th) decade, including a dementing syndrome of frontal type, a tetrapyramidal syndrome, seizures, and, in one sibling, a cerebellar syndrome. CT scan or MRI showed diffuse involvement of the white matter. The neurological signs worsened progressively leading to death within 11 and 22 months. Neuropathological examination was performed in two cases. It revealed characteristic orthochromatic leukodystrophy. In one case, the presence of pigmented macrophages and astrocytes was suggestive of Van Bogaert and Nyssen disease. However there were some atypical features including the absence of pigmented cells in the second case whose clinical course was shorter, and the cavitary appearance of the white matter changes with a relative increase in the number of oligodendrocytes raising the issue of a possible link between this condition and cavitary orthochromatic leukodystrophies.

Progressive multifocal leukoencephalopathy and oligodendroglioma in a monkey co-infected by simian immunodeficiency virus and simian virus 40.

A rhesus monkey experimentally inoculated with simian immunodeficiency virus (SIV) mac251 was killed 42 months later because of poor general condition. CD4 lymphocyte count which was 3,430/mm3 before inoculation, had decreased to 638/mm3 2 months before death. Neuropathological examination revealed changes characteristic of progressive multifocal leukoencephalopathy (PML) in the white matter of the cerebral hemispheres and brain stem. In situ hybridization was negative for JC virus but markedly positive for simian virus 40 (SV40) in the nuclei of many oligodendrocytes. Many oligodendrocytes also expressed p53. Within an area involved by PML, there was a densely cellular tumor with honeycomb appearance and elongated vessels characteristic of oligodendrogliomas. Within the tumor in situ hybridization for SV40 and immunocytochemistry for p53 were negative. Opportunistic infection by SV40 has been occasionally reported in experimentally SIV-infected monkeys resulting in PML or malignant astrocytoma. Association of JC virus-induced PML and astrocytomas has been reported in three human cases without AIDS. In those cases, as in our monkey, polyomaviruses (SV40 or JC virus) were expressed in the areas with PML but not in the glial tumor. Association of PML and oligodendroglioma has not been reported previously to our knowledge. The relationship between oligodendrocyte proliferation and polyomavirus infection of oligodendrocytes is unclear. Our findings suggest that binding of the viral protein to p53 may result in inactivation of the pro-apoptotic protein favoring the proliferation of a randomly occurring tumoral clone of oligodendrocytes.

Corneal endothelial cell apoptosis in patients with Fuchs' dystrophy.

PURPOSE: To investigate whether apoptosis plays a notable role in degeneration of corneal endothelial cells in patients with Fuchs' dystrophy. METHODS: Forty-seven corneal buttons from 41 patients with Fuchs' dystrophy were studied. Nucleus labeling, transmission electron microscopy (TEM), and TdT-dUTP terminal nick-end labeling (TUNEL) were used to detect apoptosis. TEM and TUNEL were performed on sections of all 47 corneal buttons, and nucleus labeling was performed on the last 10 corneas. Seven human donor corneas, two corneal buttons from two patients with keratoconus, and one corneal button from a patient with interstitial keratitis were used as negative controls for detection of apoptotic endothelial cells. Negative controls were studied by means of nucleus labeling, TUNEL, and TEM. RESULTS: In the nucleus labeling assay, the average percentage of apoptotic endothelial cells was 2.65% in the Fuchs' dystrophy group (n = 10) and 0.23% in the control group (n = 10; P = 0.0003). In the TUNEL assay, labeling of some endothelial cells was observed on 42 of 47 corneas in the Fuchs' dystrophy group, whereas it was absent on most specimens of the control group. In TEM, most endothelial cell nuclei had a normal appearance, and apoptotic endothelial cells featuring condensed nucleus and decreased cell size could be observed exceptionally. Some apoptotic cells were found in the basal epithelial cell layer by means of nucleus labeling, TUNEL, and TEM in the Fuchs' dystrophy group but not in the control group. CONCLUSIONS: This study suggests that apoptosis plays an important role in endothelial cell degeneration in Fuchs' dystrophy. Because of a lack of conclusive evidence of increased endothelial apoptosis by TEM, further studies are needed to ascertain this finding.

Neuronal apoptosis in human immunodeficiency virus infection.

Neuronal apoptosis has been shown to occur in HIV infection by a number of in vivo and in vitro studies, however, the cause of neuronal damage in AIDS is still unclear and its relationships with the cognitive disorders characteristic of HIV dementia remain a matter of debate. In this review, based on our experience, we analyse the techniques used to identify neuronal apoptosis on post-mortem AIDS brains and describe the relationships of neuronal apoptosis with the stage of disease, a history of HIV-dementia, the degree of productive HIV infection, microglial activation, blood-brain barrier involvement and axonal damage. We conclude that the severity of neuronal apoptosis in the cerebral cortex correlates with the presence of cerebral atrophy, but not with the cognitive disorders. There is no global quantitative correlation between neuronal apoptosis and HIV encephalitis, microglial activation or axonal damage. However we found some topographical correlation between these changes. We conclude that neuronal apoptosis and consequent neuronal loss, in HIV infected patients, are probably not related to a single cause. It seems likely that microglial activation, directly or indirectly related to HIV infection of the CNS, plays a major role in its causation possibly through the mediation of oxidative stress. Axonal damage, either secondary to microglial activation, or to the intervention of systemic factors may also contribute to neuronal apoptosis.

[A process of programmed cell death as a mechanisms of neuronal death in prion diseases]. / Un processus de mort cellulaire programmée intervient dans la perte neuronale des maladies à prions.

Neuronal loss is a salient feature of prion diseases; however, its cause and mechanism, particularly its relationship with the accumulation of the pathogenic, protease resistant isoform PrPres of the cellular prion protein PrPc, are still unclear. A number of studies suggest that it could occur through a process of programmed cell death which is consistent with the lack of inflammation in these conditions. In this paper, we review the different techniques used to identify apoptosis of neurons, and analyse the studies demonstrating neuronal apoptosis in prion diseases, either experimentally, in animal or in human. Apoptosis of rat hippocampal neurons, in cultures exposed to a synthetic peptide homologous to the prion protein, has been identified on morphological criteria after staining by a fluorescent marker of DNA and by gel electrophoresis of neuronal DNA. Apoptosis of neurons has also been identified in vivo using in situ end labelling and electron microscopy in scrapie infected mice. In human, apoptotic neurons were identified by in situ end labelling in Creutzfeldt-Jakob Disease and in Fatal Familial Insomnia. Apoptotic neurons were mostly found in damaged regions and their presence and abundance seemed to correlate closely with neuronal loss. Neuronal apoptosis also correlated well with microglial activation as demonstrated by the expression of major histocompatibility complex class II, antigens, and with axonal damage as identified by beta-amyloid protein precursor immunostaining. In contrast, there was no clear correlation between the topography and severity of neuronal apoptosis and the type, topography and abundance of prion protein deposits as demonstrated by immunohistochemistry. Similarly, within the framework of comparable phenotypes, there was no difference in the abundance and distribution of apoptotic neurons according to the aetiology whether sporadic, familial, or iatrogenic, of the disease. The pathogenetic mechanism of neuronal apoptosis remains speculative and several hypothesis have been proposed. The lack of a direct association between neuronal damage and PrPres deposition may support models of neuropathogenesis based on "loss of function" of PrPc, such as withdrawal of defined activation signals inducing programmed cell death, rather than neurotoxicity. It is also possible that PrPres is neurotoxic and the dissociation between neuronal damage and the amount of protein only reflects variations in selective neuronal vulnerability. Finally, neuronal apoptosis might be an indirect consequence of PrPres deposition. PrPres-induced dendritic or axonal damage, perhaps enhanced by consequent microglial activation, might contribute to neuronal apoptosis either due to deafferentation or to retrograde neuronal degeneration.

[Neuronal apoptosis in human prion diseases]. / Apoptose neuronale au cours des maladies à prions.

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 this 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 26 patients who died from prion diseases. They included 16 cases of Creutzfeldt-Jakob disease (5 sporadic cases, 5 familial, 3 iatrogenic, and 3 cases with the new variant), and 10 cases of fatal familial insomnia including 8 homozygotes methionine/methionone at codon 129 of the prion protein gene and 2 heterozygotes. 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 immunohistochemistry.

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.

Neuronal apoptosis does not correlate with dementia in HIV infection but is related to microglial activation and axonal damage.

To characterize the distribution of apoptotic neurons and their relationships with the stage of disease, a history of HIV-dementia, and the degree of productive HIV infection, microglial activation and axonal damage, we examined the brains of 40 patients. Samples of frontal and temporal cortex, basal ganglia and brain stem were taken post-mortem from 20 patients with AIDS (including three with HIV-dementia, and eight with cognitive disorders that did not fulfil the criteria for HIV-dementia), 10 HIV-positive asymptomatic cases and 10 seronegative controls. Neuronal apoptosis was demonstrated by in situ end labelling in 18 AIDS cases and two pre-AIDS cases; a single apoptotic neuron was present in the temporal cortex of a control. Semiquantitative evaluation showed that the severity of neuronal apoptosis in the cerebral cortex correlated with the presence of cerebral atrophy, but not with a history of HIV dementia. There was no global quantitative correlation between neuronal apoptosis and HIV encephalitis or microglial activation. However, there was some topographical correlation between these changes. In the basal ganglia, apoptotic neurons were much more abundant in the vicinity of multinucleated giant cells and/or p24 expressing cells. Microglial activation was constantly present in these areas. Axonal damage was identified using beta-amyloid-precursor protein (betaAPP) immunostaining in 17 AIDS and eight pre-AIDS brains. Although no global quantitative correlation could be established between axonal damage and neuronal apoptosis there was an obvious topographic correlation supporting the view that axonal damage, either secondary to local microglial activation or due to the intervention of systemic factors, may also contribute to neuronal apoptosis.