[Spreading of protein misfolding: A new paradigm in neurology]. / La transconformation protéique, nouveau paradigme en neurologie.

Protein misfolding and spreading ("transconformation") are being better understood. Described in Prions diseases, this new paradigm in the field of neurodegenerative disorders and brain aging also implies sporadic inclusion myositis, type 2 diabetes, some cancers, sickle cell disease... Misfolding is transmitted from a protein or peptide to a normally folded one. Often associated with a stress of the endoplasmic reticulum, it may spread along the neurites, following anterograde or retrograde axonal transport. In the central nervous system, it occurs in a few cells and there is invasion of adjacent cells by cell-to-cell spread. Three varieties of protein misfolding occur along neuroanatomical pathways. It can be a 'centripetal' process. The synucleinopathy of Parkinson disease has been carefully studied: the changes first occur in cardiac or enteric plexuses... and reach later on the mesencephalon and neocortex. Thus, skin biopsy might prove a diagnostic tool. Protein misfolding may also occur along 'centrifugal' pathways, from motor cortex to peripheral motor neurons. Examples are provided by SOD and pTDP-43 in Amyotrophic Lateral Sclerosis. Amyloid ß peptide in cerebral aging and Alzheimer's disease also spread from occipital cortex to the brainstem. Lastly, the propagation may remain 'central' for TDP-43 in behavioral variant frontotemporal dementia, following only pathways of the encephalic neural network. This has to be confirmed, however, since the spreading of some proteins (such as tau or Aß peptides) has been considered central for a long time and has proved today to involve extracerebral tissues. The complex mechanisms of protein misfolding, still in analysis, include the involvement of chaperone proteins, the formation of very toxic labile proteins molecules (oligomers?), and provide a number of new therapeutic perspectives.

Sicca syndrome and dementia in a patient with hepatitis C infection: a case report with unusual bifocal extrahepatic manifestations.

INTRODUCTION: Hepatitis C virus (HCV) infections are associated with extrahepatic manifestations in 40-75 % of cases. Sialitis and secondary Sjögren syndrome are well characterized complications of chronic HCV infections but the mechanisms (primary or secondary) leading to xerostomia are not understood. Similarly, brain lesions due to HCV can be primary or secondary but the pathology of primary HCV-related brain lesions is not well described. CASE REPORT: We report the postmortem case of a 60-year old patient initially presenting with sicca syndrome and dementia. HCV was identified in the brain but not in the salivary glands using transcription-mediated amplification (TMA). Focal sialitis was found in submandibular glands. Neuropathological examination revealed the presence of multiple dot-sized demyelination foci. CONCLUSION: Sicca syndrome is a common concern in chronic HCV infections and may be due to secondary immune mechanisms (we could not isolate HCV in salivary gland tissues). TMA had never been applied to the detection of viruses in salivary glands and neural tissues and proves to be a promising technique. Neuropathological reports in HCV infections are rare and the lesions we report may be the first characterization of the direct effect of HCV on brain cells. More cases are needed to define the full spectrum of lesions potentially caused by the direct action of the HCV on salivary glands and neural tissues.

Frontotemporal lobar degeneration: diversity of FTLD lesions.

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group including both sporadic and familial diseases, characterized by a macroscopic alteration. It may correspond to various cognitive syndromes: behavioral variant of frontotemporal dementia (bvFTD), progressive nonfluent aphasia, and semantic dementia. The neuropathologic classification is now based on identification of the protein that accumulates in neurons and glia: Tau, TAR DNA Binding Protein 43 (TDP-43), and FUsed in Sarcoma (FUS). The disorders in which the corresponding proteins accumulate have been named FTLD-Tau, FTLD-TDP, and FTLD-FUS. FTLD-Tau includes sporadic cases (e.g. Pick's disease) and Tau mutations. FTLD-TDP are subdivided within four types (A, B, C, D) according to the shape and distribution of TDP-43 positive lesions within the associative frontal cortex. The FTLD-FUS group includes atypical FTLD with ubiquitinated lesions (FTLD-U), Neuronal Intermediate Filament Inclusion Disease (NIFID) and Basophilic Inclusion Body Disease (BIBD).

Valosin-containing protein gene mutations: clinical and neuropathologic features.

BACKGROUND: Hereditary inclusion body myopathy (IBMPFD) with Paget disease of bone (PDB) and frontotemporal dementia (FTD) is a rare multisystem disorder with autosomal dominant inheritance. Recently, missense mutations in the gene encoding valosin-containing protein (VCP) have been found in individuals with IBMPFD. VCP/P97, which exerts a variety of cellular functions, plays a key role in the ubiquitin-proteasome dependent degradation of cytosolic proteins and in the retrotranslocation of misfolded proteins from the endoplasmic reticulum into the cytoplasm. METHODS: The authors describe the clinical features of two kindreds in which VCP R93C and R155C missense mutations segregate and perform a histopathologic examination of brain, muscle, bone, and liver of three subjects harboring the R155C mutation. RESULTS: Frontotemporal dementia was present in 100% of affected subjects in Family F1 and 70% in Family F2, as compared with an average of 30% in previously described IBMPFD families. In contrast, PDB was a more inconstant clinical feature. Biochemical and histopathologic data are consistent with the hypothesis that VCP R155C mutation disrupts normal VCP function, leading to diffuse accumulation of ubiquitinated proteins within the cells. CONCLUSIONS: VCP mutations are present in two families in which FTD is the most prominent symptom. The histopathologic study performed in patients harboring the R155C mutation supports the hypothesis that this mutation disrupts normal VCP function, leading to diffuse accumulation of ubiquitinated proteins within the cells. IBMPFD belongs to a class of genetic diseases associated with an alteration of the ubiquitin-proteasome system.

[Recent neuropathology of parkinsonian syndromes]. / Données récentes sur la neuropathologie des syndromes parkinsoniens.

The understanding of the molecular mechanisms underlying Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy has made significant progress in the recent years. Lewy body appears to be principally made of alpha-synuclein, a presynaptic protein. It also contains ubiquitin and some components of the proteasome: this suggests that alteration of protein catabolism may be involved in its formation. In favor of this hypothesis, it should be noted that Parkin, a protein that is mutated in autosomal recessive Parkinson disease, is a ubiquitin ligase. Immunohistochemistry has shown that alpha-synuclein accumulates not only in the cell body of the neurones (Lewy body) but also in their processes (Lewy neurites); it has emphasized the severity of the pathology in the nucleus basalis of Meynert, amygdala, CA2-3 sector of the hippocampus and cerebral cortex. Cortical Lewy bodies are not considered any more the marker of dementia with Lewy bodies: they are, indeed, found in true Parkinson disease cases. In progressive supranuclear palsy, 4 repeats tau accumulates in the cytoplasm of neurones and glia. At electron microscopy, the accumulation is made of straight filaments. It involves not only the neurones (where it is the main constituent of the neurofibrillary tangles) but also the glia. Astrocytic tuft is to day considered the morphological marker of progressive supranuclear palsy. Tau protein accumulates in the cell body of the oligodendrocyte as a "coiled body"; the protein is also integrated in the myelin sheath, when the cytoplasm of the oligodendrocyte wraps around the axon. This explains the numerous "threads" that are visible in cases of progressive supranuclear palsy. Striato-nigral degeneration, sporadic olivo-ponto-cerebellar atrophy and primitive orthostatic hypotension are various clinico-pathologic aspects of the same disorder: multiple system atrophy. It is also characterized by a morphological marker: the accumulation of alpha-synuclein in the cytoplasm of glial cells, particularly oligodendrocytes. The term synucleinopathy has been proposed to describe both idiopathic Parkinson disease and multiple system atrophy. The reason explaining the cellular topography of alpha-synuclein accumulation, neuronal in Parkinson disease, glial in multiple system atrophy is still unknown.

[Neuropathology of the cerebral vessels of centenarians]. / Neuropathologie des vaisseaux cérébraux des centenaires.

Neuropathological study of brain and brain vessels was performed in two series of 12 and 20 centenarians, focusing on the prevalence of small vessel lesions, infarction, Alzheimer's changes and mental status. These are discussed as a function of vascular risk factors. In the first series (12 cases), there was no correlation between the severity of small vessel lesions: hyalinosis (12/12), mineralisation (10/12), amyloid angiopathy (9/12), vascular risk factors (high blood pressure or diabetes), Alzheimer's lesions. However, there was a tendency for an association between amyloid angiopathy and high density of neurofibrillary tangles. In the second series (20 cases), small infarcts and lacunes were found in 9/20 cases, neurofibrillary tangles and diffuse deposits of A beta peptide were constant, senile plaques were very frequent (19/20). Five patients were demented (one vascular dementia, one Alzheimer dementia, and 3 mixed dementias). These data indicate that: 1) Lesions of the walls of small cerebral vessels do not seem linked to the vascular risk factors observed at the end of the life of centenarians. 2) Cerebral infarcts and lacunes are frequent in these patients, and are responsible, at least in part, for a high proportion of the cognitive dysfunctions. The study of larger series is needed for a better understanding of relationships between vascular and degenerative lesions in the oldest old.

Similarities between spinocerebellar ataxia type 7 (SCA7) cell models and human brain: proteins recruited in inclusions and activation of caspase-3.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant polyglutamine disorder presenting with progressive cerebellar ataxia and blindness. The molecular mechanisms underlying the selective neuronal death typical of SCA7 are unknown. We have established SCA7 cell culture models in HEK293 and SH-SY5Y cells, in order to analyse the effects of overexpression of the mutant ataxin-7 protein. The cells readily formed anti-ataxin-7 positive, fibrillar inclusions and small, nuclear electron dense structures. We have compared the inclusions in cells expressing mutant ataxin-7 and in human SCA7 brain tissue. There were consistent signs of ongoing abnormal protein folding, including the recruitment of heat-shock proteins and proteasome subunits. Occasionally, sequestered transcription factors were found. Activated caspase-3 was recruited into the inclusions in both the cell models and human SCA7 brain and its expression was upregulated in cortical neurones, suggesting that it may play a role in the disease process. Finally, on the ultrastructural level, there were signs of autophagy and nuclear indentations, indicative of a major stress response in cells expressing mutant ataxin-7.

Increase of adenomatous polyposis coli immunoreactivity is a marker of reactive astrocytes in Alzheimer's disease and in other pathological conditions.

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene are responsible for colon cancer in familial adenomatous polyposis coli and in many sporadic colorectal tumors. The product of the APC gene is also essential for normal development and is expressed in the adult brain. We have investigated the immunocytochemical localization of APC in the temporal cortex and hippocampus of normal human brain, in Alzheimer's disease (AD) and in several other neuropathological conditions. APC was expressed in neuronal cell bodies and dendrites both in control subjects and in patients with different diseases. In addition, a high APC expression was observed in a proportion of fibrillary and glial fibrillary acidic protein-positive astrocytes in AD. Furthermore, in AD the proportion of APC-positive astrocytes was higher in astrocytes associated with beta-amyloid (Abeta) deposits in senile plaques than in astrocytes not associated to Abeta deposits. APC-positive astrocytes were also observed in control cases, in diffuse Lewy body disease, in Creutzfeldt-Jacob disease, in HIV encephalitis and around cerebral infarcts. Tumoral astrocytes in pilocytic astrocytoma and in glioblastoma were also strongly APC positive. APC was not detected in cultured astroglial cells. These results indicate that APC expression is upregulated in astrocytes following their activation by several types of pathological insults and is a newly identified molecular characteristic of the reactive phenotype of astrocytes, possibly related to the control of cell proliferation. In addition, it also suggests that Abeta, and/or the inflammatory process associated with Abeta deposits, is responsible for a preferential increase of APC expression in astrocytes in AD.

Ataxin-7 interacts with a Cbl-associated protein that it recruits into neuronal intranuclear inclusions.

Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease caused by expansion of a CAG repeat in the coding region of the SCA7 gene. The disease primarily affects the cerebellum and the retina, but also many other central nervous system (CNS) structures as the disease progresses. Ataxin-7, encoded by the SCA7 gene, is a protein of unknown function expressed in many tissues including the CNS. In normal brain, ataxin-7 is found in the cytoplasm and/or nucleus of neurons, but in SCA7 brain ataxin-7 accumulates in intranuclear inclusions. Ataxin-7 is expressed ubiquitously, but mutation leads to neuronal death in only certain areas of the brain. This selective pattern of degeneration might be explained by interaction with a partner that is specifically expressed in vulnerable cells. We used a two-hybrid approach to screen a human retina cDNA library for ataxin-7-binding proteins, and isolated R85, a splice variant of Cbl-associated protein (CAP). R85 and CAP are generated by alternative splicing of the gene SH3P12 which we localized on chromosome 10q23-q24. The interaction between ataxin-7 and the SH3P12 gene products (SH3P12GPs) was confirmed by pull-down and co-immunoprecipitation. SH3P12GPs are expressed in Purkinje cells in the cerebellum. Ataxin-7 colocalizes with full-length R85 (R85FL) in co-transfected Cos-7 cells and with one of the SH3P12GPs in neuronal intranuclear inclusions in brain from a SCA7 patient. We propose that this interaction is part of a physiological pathway related to the function or turnover of ataxin-7. Its role in the pathophysiological process of SCA7 disease is discussed.

Laminar specific loss of isocortical presenilin 1 immunoreactivity in Alzheimer's disease. Correlations with the amyloid load and the density of tau-positive neurofibrillary tangles.

Presenilin 1 has been shown to be mutated in a high proportion of cases of familial Alzheimer's disease. Immunoreactive epitopes of the protein have been found mainly in neurones devoid of neurofibrillary tangles - an observation that has led to the conclusion that presenilin 1 could have a protective role. In this study, the relationship between deposits of Abeta peptide (both the 40 and 42 isoforms), tau positive neurofibrillary tangles and presenilin 1-positive neuronal profiles were analysed in three cases of presenilin 1 mutation, four cases of sporadic Alzheimer's disease and five controls. Immunohistochemistry was performed in a sample from the supramarginal gyrus. The proportion of volume occupied by the Abeta1-40 and Abeta1-42 deposits (amyloid load) was evaluated by a point-counting technique. Tau-positive neurofibrillary tangles, and presenilin 1-positive neuronal profiles were directly counted. The location of the lesions in the thickness of the cortex was recorded. The density of PS1-positive neuronal profiles in Alzheimer's disease cases was lower than in the controls. The deficit was significant only in the upper layers of the cortex. The density of presenilin 1 neuronal profiles was negatively correlated with Abeta1-40 and Abeta1-42 loads, and with the density of tau-positive neurofibrillary tangles. Multivariate analysis showed that the Abeta1-42 load was the best determinant of the decrease in presenilin 1-positive neuronal profiles. Presenilin 1-positive neurones appear to be lost rather than protected in the course of Alzheimer disease.

[Research on multiple sclerosis and tissue banks]. / Recherches sur la sclérose en plaques et banques de tissus.

Tissue banks are of major importance in research on human tissues, in particular as regards the furthering of our knowledge on multiple sclerosis (MS). Individuals who wish to make a 'donation of their brain' for autopsy, or pathologists in possession of biopsy specimens that have not been utilized for diagnosis provide the necessary material for investigation by research teams. In addition to their technical aspects, brain tissue banks provide information and aid in promoting research. Their functioning, usually supported by patient associations, has encountered certain difficulties. At present, it is challenged by a decrease in the number of autopsies.

Behavioral alterations associated with apoptosis and down-regulation of presenilin 1 in the brains of p53-deficient mice.

Presenilin 1 (PS1) expression is repressed by the p53 tumor suppressor. As shown herein, wild-type PS1 is an effective antiapoptotic molecule capable of significantly inhibiting p53-dependent and p53-independent cell death. We analyzed, at the functional and molecular levels, the brains of p53 knockout mice. Surprisingly, we found that lack of p53 expression induces apoptotic brain lesions, accompanied by learning deficiency and behavioral alterations. p53-deficient mice show an unexpected overexpression of p21(waf1) with subsequent down-regulation of PS1 in their brains. This process is progressive and age-dependent. These data indicate that the p53 pathway, besides affecting tumor suppression, may play a major role in regulating neurobehavioral function and cell survival in the brain.

Dementia following treatment of brain tumors with radiotherapy administered alone or in combination with nitrosourea-based chemotherapy: a clinical and pathological study.

A retrospective clinical and pathological study of 4 patients who developed the syndrome of radiation induced dementia was performed. All patients fulfilled the following criteria: (1) a history of supratentorial irradiation; (2) no evidence of symptomatic recurrent tumor; (3) no other cause of progressive cerebral dysfunction and dementia. The clinical picture consisted of a progressive "subcortical" dementia occurring 3-12 months after a course of cerebral radiotherapy. Examination revealed early bilateral corticospinal tract involvement in all patients and dopa-resistant Parkinsonian syndrome in two. On CT scan and MRI of the brain, the main features consisted of progressive enlargement of the ventricles associated with a diffuse hypodensity/hyperintensity of the white matter best seen on T2 weighted images on MRI. The course was progressive over 8-48 months in 3 patients while one patient had stabilization of his condition for about 28 years. Treatment with corticosteroids or shunting did not produce sustained improvement and all patients eventually died. Pathological examination revealed diffuse white matter pallor with sparing of the arcuate fibers in all patients. Despite a common pattern on gross examination, microscopic studies revealed a variety of lesions that took two basic forms: (1) a diffuse axonal and myelin loss in the white matter associated with tissue necrosis, particularly multiple small foci of necrosis disseminated in the white matter which appeared different from the usual "radionecrosis"; (2) diffuse spongiosis of the white matter characterized by the presence of vacuoles that displaced the normally-stained myelin sheets and axons. Despite a rather stereotyped clinical and radiological course, the pathological substratum of radiation-induced dementia is not uniform. Whether the different types of white matter lesions represent the spectrum of a single pathological process or indicate that the pathogenesis of this syndrome is multifactorial with different target cells, remains to be seen.

Atypical neuronal inclusion bodies in meningioangiomatosis.

A case of meningioangiomatosis not associated with neurofibromatosis 2 in a 24-year-old man is reported. Abundant neurofibrillary tangles and threads, shown by immunohistochemistry and ultrastructural analysis to be similar to those seen in Alzheimer's disease, were found in the residual neuropil. Another lesion consisting of argyrophilic globular inclusion bodies with radial fibrils was found at the periphery. Single and double immunostaining with a panel of antibodies showed similarities between these inclusions and Pick bodies.

Cerebral T2-weighted signal decrease during aging in the mouse lemur primate reflects iron accumulation.

4.7 Tesla T2-weighted magnetic resonance images showed a highly significant signal decrease in the pallidum, substantia nigra, putamen, and a less significant decrease in the thalamus and the caudate of aging mouse lemurs (Microcebus murinus). We evaluated the contribution of iron deposits to the signal decrease comparing Perls' stained histological sections of six mouse lemurs brains aged 1 to 10 years to magnetic resonance images. In young animals, none of the brain structures was stained. A large number of iron deposits were visible in the pallidum and substantia nigra of aged animals and a moderate number in the middle aged ones. In the putamen, few iron deposits were visible in aged and middle-aged animals. The thalamus and the caudate appeared unstained with Perls' technique; iron was too low to be detected. The intensification of the reaction by diaminobenzidine revealed iron deposits in the thalamus of aging animals. This study suggests that in mouse lemurs, iron deposits are responsible for T2-weighted signal decrease in the central gray nuclei.

[125I]EGF binding in basal ganglia of patients with Parkinson's disease and progressive supranuclear palsy and in MPTP-treated monkeys.

Since EGF is known to protect and stimulate the activity of dopaminergic neurons, an autoradiographic study of [125I]EGF binding sites was performed in the striatum and pallidal complex in parkinsonian syndromes. The analysis was performed on postmortem brain tissues of three control subjects, three patients with Parkinson's disease, and three patients with progressive supranuclear palsy, another parkinsonian syndrome in which dopaminergic neurons also degenerate. Since all six patients had been treated with L-Dopa, we also analyzed the effects of this drug in an animal model of Parkinson's disease. Quantitative analysis of [125I]EGF binding was performed on the brains of three control monkeys, nine monkeys rendered parkinsonian by MPTP intoxication, three of which were treated with L-Dopa. An increased density of [125I]EGF binding was observed at anterior levels in the dorsal striatum, but not in the pallidum, of patients with Parkinson's disease and progressive supranuclear palsy. [125I]EGF binding was unchanged in parkinsonian monkeys whether or not they had been treated with L-Dopa. The data suggest an increased expression of EGFRs in the striatum in chronic parkinsonian syndromes but not in acute models of the disease.

Dissociation of Alzheimer type pathology in a disconnected piece of cortex.

A woman with Alzheimer's disease died at the age of 85 years. A left sphenoid meningioma had been removed 27 years earlier. The tumor and the operation had severely altered the white matter of the frontal lobe and of the anterior part of the temporal lobe on the left side and massively disconnected a small piece of frontal cortex. There were numerous senile plaques and neurofibrillary tangles in the limbic and isocortical samples. The white matter lesions, on the operated (left) side, were associated with a lower density of neuritic plaques and of neuropil threads and with a higher density of beta-amyloid (A beta) deposits. The density of tau-positive neuritic plaques, neurofibrillary tangles and neuropil threads was close to zero, whereas the diffuse deposits of A beta were abundant, in the small disconnected piece of cortex. In this area, the white matter was severely damaged, as in the adjoining cortex, but the continuity of the cortical ribbon was also disrupted. These data show that neuritic and A beta pathologies may be dissociated and suggest that the neuritic alterations mainly involved cortico-cortical fibers coursing tangentially in the cortical ribbon.

Tumor necrosis factor-alpha, microglia and astrocytes in AIDS dementia complex.

The pathogenesis of HIV-associated cognitive changes is poorly understood. Cytokines such as tumor necrosis factor-alpha (TNF-alpha) have been postulated to contribute to the mechanism of the neurological complications of HIV infection. One of the effects of TNF-alpha is to induce astrocyte proliferation in vitro. The purpose of this study was to look for a correlation between the expression of TNF-alpha, astrogliosis and the degree of cognitive impairment in 12 prospectively assessed AIDS cases without focal brain lesion, 8 of whom were demented. They were compared with 6 control patients without neurological disease. Neuropathological examination showed myelin pallor in 5 of the 8 demented patients. TNF-alpha expression was detected by immunohistochemistry in the midfrontal cortex, subcortical and deep white matter, and basal ganglia. Not only perivascular macrophages but also some microglial and endothelial cells were labeled. Most TNF-alpha-positive cells were in close contact with glial fibrillary acidic protein-positive astrocytes. They were more numerous than gp41-positive cells. Their density increased with increasing cognitive impairment and in parallel to the astrogliosis in the frontal cortex, basal ganglia and deep white matter. These findings further support the hypotheses that lesions of the deep white matter, driven by TNF-alpha, are associated with cognitive alteration, and that indirect effects of HIV infection in the brain participate in the development of HIV-associated dementia through a diffuse immune activation, mediated by cytokines.

[Is the topography of Alzheimer's disease lesions a clue to their pathogenesis?]. / La topographie des lésions de la maladie d'Alzheimer permet-elle de soupçonner leur mécanisme?

Neurofibrillary changes, labelled by antitau antibodies and deposits, labelled by anti-A beta antibodies, were counted in 6 cortical areas in 29 prospectively studied cases (Charles Foix Longitudinal Study). The intellectual status had been assessed by the Blessed test score; 10% of the cases were found to be normal (score > 27), 10 other percents were deeply demented (score < 2) and the other cases were regularly distributed over the intermediate values. Tau positive neurofibrillary changes were present in the hippocampus and in the parahippocampal gyrus even in intellectually normal cases. They were found in a primary sensory cortex (the visual cortex) only in the most severely affected cases. Associative cortices were spared in the normal cases and in the least demented patients. They were involved only at a critical value of the Blessed Test Score. A beta deposits involved more areas than the neurofibrillary pathology and their distribution was less systematically organized. Their density was poorly correlated with the intellectual status. Neuritic plaques, made of an amyloid core and of a crown of tau positive neurites, were present only in those areas that also contained neurofibrillary tangles. Our findings support the contention that neurofibrillary pathology, involving a set of short range, "feed-backward", cortico-cortical connections, is a close correlate of dementia. The role of A beta deposits remains unclear. Although poorly connected with dementia, they could be the remote initiator of the pathological cascade that leads to the neurofibrillary pathology, immediate cause of the cortical dysfunction.