Search

Cholesterol is a lipid found in every animal cell and is necessary for its survival. Among its multiple roles in the body, it is a component of cell membranes that is crucial for the maintenance of their structure and fluidity and is thus implicated in the modulation of many signalling pathways. Neurons are especially dependant on cholesterol input since the proper composition of their plasma membrane is required for vesicular exocytosis of neurotransmitters and transduction of the post-synaptic signal. It has been shown that both an excess and a lack of cholesterol is neurotoxic. Moreover, many neurodegenerative diseases, such as Alzheimer’s or Huntington’s disease, have been associated with dysregulation of cholesterol homeostasis, highlighting the need for a fine regulation of its metabolism in nervous tissues. Coordinated actions of neurons and glia, that exhibit complementary functions, are mandatory in that respect. In the brain, astrocytes, the main macroglial cells, may be the major source of cholesterol biosynthesis and export. Neurons, acting as consumers, may be specifically in charge of cholesterol elimination via conversion into 24S-OHC by the CYP46A1 enzyme. This metabolite is likely not only an elimination product of cholesterol but also a signalling molecule in glial cells. It might enable glial cholesterol metabolism to adjust as needed and avoid an overload in brain tissues. In the retina, cholesterol metabolism and its regulation under physiological and pathological conditions remain largely unknown. Müller cells, the major macroglial cells of the retina, could participate in cholesterol synthesis in this tissue even though evidence is still needed. Regarding 24S-OHC, its synthesis is mainly restricted to retinal ganglion cells, neurons responsible for nervous signal transmission from the retina to the brain. Studies performed in our laboratory suggest that CYP46A1 and its product could be implicated in the physiopathology of glaucoma, a disease characterized by ganglion cell degeneration.The present project aims to provide a better understanding of cholesterol metabolism in Müller cells and its potential regulation by 24S-OHC. The goal is also to unveil changes in cholesterol metabolism during the progression of glaucoma by characterizing, at different time points, the molecular players implicated in its biosynthesis, transport and elimination. Our experiments performed on primary Müller cell cultures indicate that these cells possess the molecular machinery to synthesize and export cholesterol and could therefore actively participate in its metabolism in the retina. We also reported a strong hypocholesterolemic effect of 24S-OHC in Müller cells, reinforcing the hypothesis that this compound could be a regulator of cholesterol metabolism in the retina. In an experimental glaucoma model, induced by an elevation in intraocular pressure in rats, we observed major changes in cholesterol metabolism. At the earliest time points, genes implicated in cholesterol biosynthesis and uptake in the retina were upregulated, and cholesterol precursor levels were consecutively and transiently elevated. An important component of our work was to demonstrate that counter-regulatory mechanisms were activated in response to these initial dysregulations, that enabled the maintenance of cholesterol homeostasis in the retina and likely participated in ganglion cell survival., Le cholestérol est un lipide présent dans toutes les cellules animales et indispensable à leur survie. Parmi les rôles multiples qu’il joue dans l’organisme, celui de composant des membranes cellulaires est essentiel pour le maintien de leur structure, de leur fluidité et donc clé dans la modulation de nombreuses voies de signalisation. A ce titre, les neurones sont particulièrement dépendants de l’apport en cholestérol car l’intégrité de la composition de leur membrane est requise pour l’exocytose vésiculaire des neurotransmetteurs et la transduction du signal post-synaptique. Ainsi, il a été montré qu’un excès ou un défaut de ce composé est neurotoxique. De nombreuses maladies neurodégénératives, comme la maladie d’Alzheimer, ont d’ailleurs été associées à des perturbations de l’homéostasie du cholestérol, soulignant la nécessité d’une régulation fine de son métabolisme dans les tissus nerveux. Dans ce cadre, l’existence de mécanismes de coordination entre les actions des neurones et de la glie, dont les fonctions sont complémentaires, semble indispensable. Dans le cerveau, les astrocytes, cellules macrogliales majoritaires, seraient le principal lieu de synthèse et d’export du cholestérol. Les neurones, plutôt consommateurs, seraient spécifiquement en charge de son élimination, via sa conversion en 24(S)-hydroxycholestérol (24S-OHC) par l’enzyme CYP46A1. Ce métabolite ne serait pas seulement un produit d’excrétion du cholestérol, mais jouerait également le rôle de molécule signal dans les cellules gliales. Il permettrait d’adapter le métabolisme de la glie aux besoins en cholestérol, afin d’éviter toute surcharge dans les tissus cérébraux. Dans la rétine, le métabolisme du cholestérol et sa régulation, en condition physiologique et pathologique, sont encore peu décrits. Les cellules de Müller, macroglie majoritaire de la rétine, pourraient participer à la synthèse de cholestérol dans ce tissu, mais les arguments dans ce sens méritent d’être étoffés. Concernant le 24S-OHC, sa synthèse est essentiellement restreinte aux cellules ganglionnaires, neurones chargés de transmettre l’influx nerveux de la rétine au cerveau. Les résultats de quelques études menées au laboratoire suggèrent d’ailleurs que l’enzyme CYP46A1 et son métabolite seraient impliqués dans la physiopathologie du glaucome, maladie liée à la dégénérescence des cellules ganglionnaires.Le but de ce projet de thèse est de contribuer à une meilleure compréhension du métabolisme du cholestérol dans les cellules de Müller et son éventuelle régulation par le 24S-OHC. L’objectif était également de mettre en évidence de potentielles altérations du métabolisme du cholestérol au cours du glaucome en caractérisant, à différents points de temps, les acteurs moléculaires impliqués dans sa synthèse, son transport et son élimination.Nos expériences menées sur des cultures primaires de cellules de Müller indiquent que ces cellules possèdent la machinerie moléculaire pour synthétiser et exporter le cholestérol, et pourraient donc participer activement à son métabolisme dans la rétine. Nous avons également décrit un effet hypocholestérolémiant du 24S-OHC dans les cellules de Müller, ce qui renforce l’hypothèse selon laquelle ce composé pourrait intervenir dans la régulation du métabolisme du cholestérol dans la rétine. Dans un modèle de glaucome expérimental, par hyperpression oculaire chez le rat, nous avons observé des modifications majeures du métabolisme du cholestérol. De manière très précoce, il s’agit d’une surexpression des gènes impliqués dans la synthèse et la captation de cholestérol dans la rétine, puis d’une élévation transitoire des taux de ses précurseurs. Un élément important de notre travail a été de montrer que ces perturbations initiales sont suivies de l’activation de mécanismes de contre-régulation coordonnés, permettant de maintenir l’homéostasie du cholestérol dans la rétine et participant donc sans doute positivement à la survie des cellules ganglionnaires.

International audience; Langerhans cell histiocytosis (LCH) is a rare multisystemic disease. LCH is characterized by proliferation of myeloid progenitors with altered differentiation program and similar phenotypic features to epidermal dendritic cells termed Langerhans cell. LCH cells express CD1a+ and langerin and exhibit BRAF V600E mutation in ∼ 50% of cases. Neurological involvement or neuro-LCH is observed in 5 to 10% of cases. Three subtypes of neuro-LCH are individualized. The tumor type, accounting for 45% of neuro-LCH, affect mainly young adults. Tumor neuro-LCH is characterized by space occupying lesion(s) with contrast enhancement on MRI. Clinical symptoms are due to tumor brain location(s). Pathological examination of tumor neuro-LCH lesions reveals typical features of LCH. Treatment relies on surgical resection with/without chemotherapy. Degenerative neuro-LCH, accounting for 45% of cases, is usually revealed, mostly in children, by: (i) a cerebellar syndrome, (ii) a pyramidal syndrome, (iii) a pseubulbar palsy, and/or (iv) cognitive disorders. On MRI, several signs may coexist: (i) cortex atrophy, (ii) white matter T2 hyperintensities, and (iii) deep gray matter T1 hyperintensities. Pathological analysis of degenerative neuro-LCH lesions have been rarely performed and have never detected CD1a+ histiocytes but unspecific lesions (i.e. gliosis, neuronal loss and/or demyelination). Treatment of degenerative neuro-LCH patients is poorly standardized and poorly efficient. Functional rehabilitation and socio-educational care of these young patients are crucial. The mixed subtype of neuro-LCH combines clinico-radio-pathological characteristics of the first two first forms in the same patient, and represents 10% of neuro-HL. Neuro-HL, therefore, includes three very distinct entities with epidemiological, clinical, radiological and histological specific features requiring specific medical management.; L’histiocytose langerhansienne (HL) est une maladie multisystémique rare. L’HL est correspond à une prolifération de cellules myéloïdes progénitrices au programme de différenciation altéré et au phénotype proche de celui des cellules dendritiques épidermiques, les cellules de Langerhans. Les cellules de l’HL sont caractérisées par l’expression de CD1a et de la langerin et par la présence (∼ 50 %) de mutation du gène BRAF. L’atteinte neurologique ou neuro-HL est observée dans 5 à 10 % des cas. Trois formes de neuro-HL sont individualisées. La forme tumorale, représentant 45 % des neuro-HL, touche l’adulte jeune. Elle se caractérise un ou (des processus) expansif(s) intracrânien(s) prenant le contraste à l’IRM. Les manifestations neurologiques sont en rapport avec la (ou les) localisation(s) lésionnelle(s). L’analyse histologique des lésions neurologiques retrouve les caractéristiques de l’HL. Le traitement repose sur la chirurgie et/ou la chimiothérapie. La forme dégénérative, représentant 45 % des cas, se manifeste, principalement chez l’enfant, par un syndrome cérébello-spasmodique, un syndrome pseudobulbaire et/ou des troubles neuropsychologiques. À l’IRM cérébrale, on observe dans la forme complète : (i) une atrophie corticale, (ii) des hypersignaux T2 de la substance blanche et (iii) des hypersignaux T1 de la substance grise profonde. Les analyses histologiques des lésions cérébrales, bien que rares, n’ont jamais mis en évidence d’histiocytes CD1a+ caractéristiques de la maladie mais des lésions aspécifiques de gliose, de perte neuronale, et/ou de démyélinisation. Le traitement est peu codifié et d’efficacité modeste. La rééducation fonctionnelle et la prise en charge socio-éducative, de ces jeunes patients, sont cruciales. La forme mixte combine les caractéristiques clinicoradiopathologiques des deux premières formes chez le même patient, et représente 10 % des neuro-HL. Les neuro-HL regroupent donc trois entités très distinctes sur le plan épidémiologique, clinique, radiologique et histologique nécessitant des prises en charge spécifiques.

Serious leukoencephalopathy can be related to heroin injection or inhalation.We report the first case of leukoencephalopathy observed three weeks after a 46-year-old man sniffed heroin. The clinical presentation included cognitive and behaviour disorders, pyramidal irritation and slight gait instability. Blood and cerebrospinal fluid analyse were normal. Brain magnetic resonance imaging showed diffuse, symmetrical supratentorial white matter lesions producing high intense signals on FLAIR and b1000-weighted sequences. Proton spectroscopy revealed an increased rate of cholin, in favour of active demyelinated lesions. Brain biopsy showed intramyelinic oedema with reactive gliosis. After two and a half years, moderate attentional fluctuations and difficulties in initiating activities persisted. Repeated MRI showed a reduction of the leukoencephalopathy.Heroin could be a cause more common than thought of leukoencephalopathy. The clinical and radiological expression and prognosis could be related to the mode of consummation (inhalation, intravenous injection, sniffing). This parameter may modulate severity and localization of brain lesions. More systematic use of MRI for patients with psychiatric symptoms after heroin intoxications could lead to a better evaluation of heroin-related neurotoxicity and potentially improve prevention.

The unilateral idiopathic leopard-spot lesion of the retinal pigment epithelium is a rare and acquired entity of the young adult whose clinical description is quite recent. This pathology presents a strong proliferative potential that is both neovascular and fibroglial. The authors report a case with severe fibroglial complications. Careful follow-up of these patients and their descendants seems to be essential in order to better characterize this lesion whose nature and etiopathogeny are still unknown.

Morning Glory syndrome, characterized by an enlarged dysplasic optic disc with glial tissue, is one of the congenital anomalies of the optic nerve. This syndrome is rare, prevalent in the girls, and generally unilateral. It can be revealed with nystagmus, strabismus, or amblyopia.We report the clinical observation of a 2.5-year-old girl, referred for the diagnosis of Morning Glory syndrome in the left eye with severe amblyopia (1/10 Rossano 1/20) and esotropia. This syndrome has associated central nervous system anomalies with a basal encephalocele. Treated with functional amblyopia therapy, visual acuity was 7/10 Rossano 1/2 after 1 year.Rehabilitation on functional amblyopia in organic optic nerve anomalies is essential. A child with a Morning Glory syndrome, detected during the period of sensory maturation, must be treated with occlusion therapy, followed by maintenance treatment. This part of the treatment can prevent deep amblyopia. Moreover, regular ophthalmologic follow-up to detect complications of retinal detachment and multidisciplinary follow-up to detect a cytogenetic disease, CHARGE syndrome, or association with endocrine and central nervous system anomalies are necessary.The author recommends occlusion therapy for children with Morning Glory syndrome or other organic asymmetric optic nerve anomalies, during the period of amblyopia reversibility. Most patients' vision improves after treatment. This case is an illustration.

Arteriovenous malformations (AVM) are congenital abnormalities that consist of tangled masses of tortuous arteries, veins and abnormal connecting channels, that apparently result from the lack of development of the local capillary bed. Because of their propensity to bleed, arteriovenous malformations clinically constitute the most significant group of vascular malformations and the most frequent type in surgical specimens. On histologic study, the lesion is composed of arteries with muscular and elastic laminae, veins dilated by the pressure to which they are exposed because of the shunting and ambiguous vessels with both arterial and venous characteristics called arterialized veins. The pathological blood vessels are separated by brain parenchyma that often shows gliosis and hemosiderin pigmentation. The histologic composition of AVM generally permits confident recognition. The pathogenesis of vascular malformations likely involves the abnormal assembly, differentiation of vascular smooth muscle cells in association with dysmorphic vessel wall. AVM exhibit distinct pattern of expression of molecular markers of differentiation and maturity of VSMC as well as vascular endothelial growth factors and their receptors.

Cognitive disorders associated with HIV infection may be due to focal lesions (lymphoma, toxoplasmosis, progressive multifocal leukoencephalitis, etc.), metabolic encephalopathy (e.g. hepatic insufficiency) or psychiatric disorders (depression). In the absence of such causes a "cognitive and motor syndrome associated with HIV infection" has been defined on clinical criteria (Working group of the American Academy of Neurology, 1991). This syndrome is not consistently associated with any specific lesion. Neither the multifocal encephalitis of HIV or CMV infection nor the diffuse leukoencephalopathy associated with HIV are the only causes. The existence of a neocortical neuronal loss has been suggested by several retrospective studies, but our prospective study has not shown cortical or subcortical atrophy. Measurement of neuronal density in Brodmann's areas 4,9 and 40 has not revealed a significant loss either global, by layer, or by column. The only constant lesion was gliosis of the cortex and white matter. Neuronal loss, therefore, is not indispensable to the occurrence of cognitive disorders in AIDS. The mechanism of dementia might be: dysfunction of cortical neurons (dendritic abnormalities, virus/neurotransmitter competition); subcortical dysfunction, as suggested by the high density of microglial nodules in that region; white matter lesions which could be due to abnormalities in the blood-brain barrier. The expression of cell adhesion molecules (VCAM-1, VLA-4, ICAM-1 and LFA-1) by endothelial cerebral cells is not significantly different in AIDS patients, demented or not, and in patients with multiple sclerosis. In contrast, the expression of VCAM-1 by astrocytes is significantly increased in demented AIDS patients compared with non demented ones.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to evaluate the diagnostic and prognostic value of MRI in the very early stages of HIV infection, we have compared the results of postmortem brain MRI and neuropathological studies in 7 asymptomatic HIV seropositive individuals, 8 seronegative controls with similar cause of death and 6 patients who died of AIDS in the absence of focal cerebral changes (opportunistic infection or tumour). Cerebral atrophy was consistently evaluated by both techniques. Seropositive asymptomatic cases were significantly more atrophic than the seronegative controls and significantly less atrophic than AIDS patients. Small high signal intensity areas in the white matter and basal ganglia were not significantly more frequent in seropositives than in seronegatives. No corresponding lesion was found at neuropathological examination. Diffuse myelin pallor of the cerebral white matter on myelin preparation was somewhat more severe in seropositive asymptomatic cases than in seronegative controls and less than in AIDS cases. However, these differences were not statistically significant. No significant correlation could be found between neuropathological myelin pallor and diffuse signal abnormalities of the white matter on MRI. We conclude that brain abnormalities are present at the early asymptomatic stage of HIV infection. These include vasculitis with opening of the blood brain barrier and consequent myelin pallor and gliosis of the white matter, and moderate brain atrophy. However MRI correlates are discrete or non specific on post mortem examination, and some probably correspond to scars of transient vascular inflammation. It is very unlikely that MRI examination has any diagnostic or prognostic value at the early stages of the disease.

A 36 year-old patient presented with a dementia of frontal type, gait disturbances, incontinence and a pseudo-bulbar palsy, which caused death at age 40. Brain biopsy of the frontal lobe showed an extensive deep subcortical gliosis. A high level of GFAP was detected by immunoblotting in the biopsy. Clinical and neuropathological observations are similar to cases described as Neumann Progressive Subcortical Gliosis. Single Photon Emission Computer Tomography showed a bilateral frontotemporal hypoperfusion, and Magnetic Resonance Imaging large periventricular and subcortical hyperintensities in both hemispheres, the brainstem and the cerebellum. The hyperintensities on T2-weighted MR images might be related to the intense gliosis. The contribution of such imaging data to diagnosis must be confirmed by other clinico-pathological cases.

Hippocampal sclerosis is a complex combination of neuronal and glial changes. It is frequently associated with temporal lobe epilepsy. Six hippocampal specimen were obtained from patients operated on for intractable mesial temporal lobe epilepsy. Comparisons were made with six autopsy controls. The neuronal and glial cells populations were studied by morphometric quantitative analysis. The glial cell types were identified by immunohistochemistry procedures. Distribution of the central (neuronal location) and the peripheral (glial location) benzodiazepine (BZ) binding sites was studied by quantitative autoradiography using [3H]-flumazénil and [3H]-PK11195 as respective ligands. Neuronal death and glial proliferation with the usual HS pattern were confirmed in all cases. Microglial cells, labelled with KP1 antibody (resident component) and with HLA-DR alpha (reactive component) were qualitatively similar in patients and controls. Particular radial organization of numerous, long and thin astrocytic processes, as labelled with GFAP antibody, was observed in the molecular layer of the dentate gyrus in 5 cases. These fibrillary processes were intermingled with the granule cells, which were markedly dispersed in 4 of the cases. In comparison with control group, all the epileptic cases had significant selective decreased central-type and increased peripheral-type BZ receptor. These results were respectively correlated with neuronal loss and glial proliferation. Morphologic results suggest that a specific configuration of astrocytic cell processes may be associated with some of the neuronal changes of human HS. Such aspect has not been reported in the astroglial growth observed in animal models of limbic epilepsy. The lack of reactive microglia suggested the absence of recent cell death.(ABSTRACT TRUNCATED AT 250 WORDS)

We report the case of a 59-year old right-handed woman presenting with progressive aphasia without any other neurological deficit and characterized by anomia, agramatism and auditory comprehension difficulties. CT scan showed no abnormalities. Four years later, aphasia was complete but neurological examination was normal. CT scan disclosed a mild cortico-subcortical cerebral atrophy with slight widening of both sylvian fissures. The results obtained with the Wisconsin Card Sorting Test and the Raven's Matrices showed only minor deficits. The IQ (WAIS) was 90. During the following 6 years the patient remained fully self-sufficient and carried out her homework normally. At that time MRI showed progression of cerebral atrophy more pronounced on the left side. Besides a rapid deterioration, twelve months later she developed severe dementia and died 13 years after the onset of the illness. Brain examination disclosed a severe atrophy (brain weight: 880 g) prominent in both frontal lobes and in the anterior perisylvian structures, more pronounced on the left side. There were no vascular lesions. Microscopy revealed widespread neuronal loss and astrocytic fibrillary gliosis confined to cortical areas and vacuolation in the superficial layers. Neurofibrillary tangles and neuritic plaques were found in the most atrophic areas but not in sufficient number to fulfill the histological criteria for Alzheimer's disease. There were no neuropathological changes of Pick's disease or subcortical degeneration. Previous microscopical studies of primary progressive aphasia showed non specific, mostly lobar atrophy similar to that observed in our case, although Alzheimer, Pick and Creutzfeldt-Jakob diseases have been reported. This neuropathological heterogeneity confirms that progressive aphasia is a non-specific language disorder mostly observed in lobar forms of brain degeneration.

Since it was discovered, twenty years ago, the glial fibrillary acidic protein has been the subject of more than 500 publications. The huge interest it has raised up is probably due partly to its abundance in the central nervous system and also, above all, to its cellular specificity which makes it the universally recognized marker of astrocytes. It has been used by biologists as a tool to follow the normal or pathological glia cell differentiation in animal models and human pathology, particularly in the fields of neuropathology and neuro-oncology.

From a neurobiological point of view, three aspects have to be considered when elaborating a therapeutic strategy to improve functional recovery after an acute lesion of the central nervous system: prevention of secondary neuronal death and axonal lesions, stimulation of nerve cells regeneration and neuronal replacement by grafting. Two aspects of our research program will be discussed in this lecture: 1. The pathophysiology of secondary neuronal death. We will focus on a neuronotoxic activity released by astrocytes and whose presently established properties suggest its involvement in the pathophysiology of secondary cell death. These data open new prospects for the pharmacological approach of neuroprotection. 2. The pathophysiology of astrogliosis: our data suggest that the neuronal control of type one astrocytes proliferation is twofold: normal neurons release a proliferation inhibition factor (a 17 Kd protein for which we suggest the name astrostatine) while injured neurons release one or several astroglial mitogens.

Four teenagers with partial epileptic seizures presented focal cortical enhanced CT scan images. Angiographies were normal. Stereotactic biopsies revealed astrocytic proliferation. CT scan abnormalities diminished or vanished in some months. On long-term follow-up seizures were either less frequent or disappeared. None of the possible aetiologic hypotheses (astrocytoma, encephalitis, sarcoidosis, multiple sclerosis, vascular malformation) was fully satisfying. Nevertheless, a regressive evolution observed in these four patients demonstrates that acquired epileptogenic lesions during adolescence are not always of poor prognosis.

The lesions of the spinal cord and the medulla in ALS, have been known for a long time. However the existence of cortical lesions in this disease, and their description, remain debated questions. This study deals with ten anatomical cases of ALS, with a special attention to the precentral gyrus. Three kinds of lesions are described in most cases: a disappearance of Betz cells with shrinkage and ghost cells of some other neurons; principally a subcortical gliosis, and also a laminar spongiosis located in the second cortical layer. The value and the signification of these lesions, which are strictly located in the motor cortex, are discussed. This could be compared to diffuse cortical lesions which are described in some cases of ALS with dementia state.

Hereditary spongiform dystrophy in young children is characterised by macrocephaly with spasticity, convulsions and ultimately a decerebrate state and diffuse electroencephalographic changes. Histological examination of the brain remains essential for its diagnosis. A review of the ultrastructural studies reported by various authors complements the findings obtained by conventional histology. We have thus endeavoured to determine whether van Bogaert-Bertrand's disease is to be considered as congenital or acquired. The anatomical findings in 3 cases together with the descriptions of other authors lead us to the following conclusions: -that the spongiform changes may be due to an osmolar disequilibrium in which the ATPase-Na/K relation with mitochondrial abnormalities is yet unclear. -that the constant finding of Alzheimer type II cells is certainly an indication of intra-astrocytic malfunction. -that the oedema blocks both myelin synthesis and its coiling into lamellae. Case 1, which showed a long survival compared to others described (about 4 years), enabled us to study terminal lesions. Sub-cortical zones, in both cerebrum and cerebellum, contained neither myelin nor spongiform cavities, but, on the other hand, showed a compact glio-fibrillosis with large vesicles and oligodendroglia of increased density. We have interpreted these lesions, progressively replaced by spongiosis deeper in the cortex, as evidence of retracted scar tissue. Differences found between cerebral weights seem to confirm this hypothesis.

The case of a 70 year-old patient with familial dementia is reported. A cerebral biopsy and neurotransmitters dosages in CSF and brain tissue ruled out a primary dementia as Pick's or Alzheimer's disease. Our case may be related to Neumann's cases of subcortical gliosis.

A 34-year-old man developed cerebellar symptoms, palatal myoclonus and spastic paraparesis progressing over several months. During this period, acute respiratory failure occurred in two instances with evidence of central chronic hypoventilation. CT scan showed enlargement of the frontal horns and posterior fossa cisterns. Post mortem examination revealed the following features: 1) Rosenthal's fibers widespread throughout the CNS but especially in subependymal regions; 2) bilateral white matter cavitations involving the frontal lobes, hilum of dentate nuclei and bulbar pyramids; 3) microscopic pseudogliomatous foci present in several sites, especially in the fornix and midbrain tegmentum; 4) the medulla and high cervical spinal cord showed "peripheral type" myelin fibers along with Schwann cell proliferation in aberrant intra-parenchymal situation. The relationship of this case--as well as the few previous adult reports--to the well-defined infantile Alexander's disease is discussed. The possible hamartomatous nature of both glial changes and aberrant myelin production is emphasized. These various lesions, including Rosenthal fiber formation, are assumed to result from a similar--probably dysontogenetic--pathophysiological mechanism. It is suggested that Alexander's disease, in this case, should be classified among phakomatoses rather than enzymopathic leukodystrophies.

AOPC is frequently associated with degeneration in other systems, the striato-nigral in particular. Three anatomical-clinical cases of AOPC complicated by striato-nigral degeneration of varying gravity are described. Case 1 had a complex history: rigidity with axial predominance, plus signs in neurovegetative system, ocular palsy, myoclonia and fasciculation and a massive atrophy of the olivo-ponto-cerebellar and striato-nigral systems. Case 2 presented as a static and kinetic cerebellar syndrome; the anatomical confirmation of the AOPC involvement showing a patchy nigro-striatal degeneration but without clinical signs. Case 3 evolved as a Parkinson-type syndrome differentiated from true Parkinson's disease by signs affecting the pyramidal system and the relative importance of static signs, the lesions then involving namely the striato-nigral system. 69 allied cases in the literature are referred to and commented upon demonstrating the great clinical and anatomical variation in presentation of AOPC. The concept of "multiple system atrophy" allows most cases to be grouped under a general heading. The degenerative diseases of the CNS, in so far as their etiology remains obscure, make up a "waiting list".

Lateralis dorsalis nucleus of thalamus belong to the limbic system of Papez more by its trigonal than cingular afferent pathways. Its parietal efferent pathways are probable, its cingular and trigonal ones possible but not proved. Neuropathologic studies provide informations to separate a latero-ventral part connected with parietal cortex and a mediodorsal part connected with limbic system.