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Biomedical subjects

Jean-Jacques Hauw

Publications and source records attributed to Jean-Jacques Hauw.

At least 19 recordsLinked to original sources
PubMed2006

V180I mutation of the prion protein gene associated with atypical PrPSc glycosylation.

A valine to isoleucine mutation at residue 180 was identified in a French patient with Creutzfeldt-Jakob disease (CJD). The mutation is located in the close vicinity of one of the two N-glycosylation sites of the cellular prion protein (PrP(C)). Western blot analysis revealed accumulation in the brain of the pathogenic proteinase K-resistant PrP (PrP(Sc)) isoform with the notable absence of the diglycosylated band. The mutant protein expressed in CHO cells was correctly glycosylated, suggesting that the atypical glycosylation pattern of PrP(Sc) was not due to the mutation at position 180. These results suggest that the diglycosylated form of the mutant PrP(180I) prevents its conversion into the pathogenic mutant form PrP(Sc180I), supporting a central role of N-linked glycan chains in the PrP conversion process.

Animals↗
PubMed2006

Familial Creutzfeldt-Jakob disease with an R208H-129V haplotype and Kuru plaques.

OBJECTIVE: To report the clinical and neuropathological features in the first patient seen, to our knowledge, with familial Creutzfeldt-Jakob disease and an R208H mutation associated with a Val/Val homozygosity at codon 129 in the prion protein gene (PRNP) and a type 2 protease-resistant prion protein. PATIENT AND RESULTS: A 61-year-old man with a long-standing history of memory loss and emotional disorders had an obvious behavioral change. Then he developed cerebellar ataxia, followed by cognitive decline. He had no myoclonus. Electroencephalography showed slow activity, and 14-3-3 protein detection was negative. Finally, the patient developed akinetic mutism and died 7 months after the onset of ataxia. Neuropathological examination showed severe spongiform changes in the frontal cortex and striatum and gliosis in the striatum and thalamus. Kuru plaques were noted in the cerebellum, notably in the molecular layer. Immunohistochemical findings showed granular, synaptic, perineuronal, and perivacuolar staining with antiprion antibodies. Kuru plaques were also stained. CONCLUSION: This study strengthens the linkage of the R208H mutation to Creutzfeldt-Jakob disease and points to some particular features such as Kuru plaques and long-standing psychiatric signs.

Amyloid↗
PubMed2006

Motor score of the Unified Parkinson Disease Rating Scale as a good predictor of Lewy body-associated neuronal loss in the substantia nigra.

BACKGROUND: How well the motor symptoms assessed by the motor section of the Unified Parkinson Disease Rating Scale (UPDRS3) reflect the neuronal loss observed in the substantia nigra is not known. OBJECTIVE: To study the relationships among the motor symptoms assessed by the UPDRS3, Lewy body-associated neuronal loss in the substantia nigra, and duration of disease. DESIGN: Longitudinal, prospective, clinicopathological study. SETTING: Long-term care facility of a university hospital. PATIENTS: Eighteen elderly patients with a parkinsonian syndrome, studied prospectively but selected post mortem on the basis of the presence of Lewy bodies, and 5 age-matched control subjects. METHODS: One map of a section of the substantia nigra, indicating the location of all the nucleolated neuronal profiles, was drawn for each case. Neuronal density was estimated using a tessellation method. The relationship between time and neuronal loss and between neuronal loss and motor symptoms (assessed by the UPDRS3) was studied by means of regression analysis, using linear and exponential models. RESULTS: The neuronal density was linearly linked with the UPDRS3 score (r = -0.83 [P<.001]). Each point added to the UPDRS3 score corresponded to an estimated loss of 25 neurons/mm(3). The density of neuronal profiles in the substantia nigra decreased exponentially with time (r = -0.73 [P<.001]). Extrapolation of the curve suggested a presymptomatic phase of 5 years. CONCLUSION: The UPDRS3 score is linearly linked to neuronal density, which, in Lewy body diseases, decreases exponentially with time at a similar pace in this series of elderly patients and in the younger patients described in the literature.

Aged↗
PubMed2006

Interlaboratory comparison of assessments of Alzheimer disease-related lesions: a study of the BrainNet Europe Consortium.

This interlaboratory study evaluated the reproducibility of the assessments of neuritic plaques and neurofibrillary tangles (NFTs)--the hallmark lesions of Alzheimer disease--and compared the staining between the BrainNet Europe centers. To reduce the topography-related inconsistencies in assessments, we used a 2-mm tissue microarray (TMA) technique. The TMA block included 42 core samples taken from 21 paraffin blocks. The assessments were done on Bielschowsky and Gallyas silver stains using an immunohistochemical (IHC) method with antibodies directed to beta-amyloid (IHC/Abeta) and hyperphosphorylated tau (IHC/HPtau). The staining quality and the assessments differed between the participants, being most diverse with Bielschowsky (good/acceptable stain in 53% of centers) followed by Gallyas (good/acceptable stain in 57%) and IHC/Abeta (good/acceptable stain in 71%). The most uniform staining quality and assessment was obtained with the IHC/HPtau method (good/acceptable stain in 94% of centers). The neuropathologic diagnostic protocol (Consortium to Establish a Registry for Alzheimer Disease, Braak and Braak, and the National Institute of Aging and Reagan [NIA-Reagan] Institute) that was used significantly influenced the agreement, being highest with NIA-Reagan (54%) recommendations. This agreement was improved by visualization of NFTs using the IHC/HPtau method. Therefore, the IHC/HPtau methodology to visualize NFTs and neuropil threads should be considered as a method of choice in a future diagnostic protocol for Alzheimer disease.

Aged↗
PubMed2006

Differentiation of sCJD and vCJD forms by automated analysis of basal ganglia intensity distribution in multisequence MRI of the brain--definition and evaluation of new MRI-based ratios.

We present a method for the analysis of basal ganglia (including the thalamus) for accurate detection of human spongiform encephalopathy in multisequence magnetic resonance imaging (MRI) of the brain. One common feature of most forms of prion protein diseases is the appearance of hyperintensities in the deep grey matter area of the brain in T2-weighted magnetic resonance (MR) images. We employ T1, T2, and Flair-T2 MR sequences for the detection of intensity deviations in the internal nuclei. First, the MR data are registered to a probabilistic atlas and normalized in intensity. Then smoothing is applied with edge enhancement. The segmentation of hyperintensities is performed using a model of the human visual system. For more accurate results, a priori anatomical data from a segmented atlas are employed to refine the registration and remove false positives. The results are robust over the patient data and in accordance with the clinical ground truth. Our method further allows the quantification of intensity distributions in basal ganglia. The caudate nuclei are highlighted as main areas of diagnosis of sporadic Creutzfeldt-Jakob Disease (sCJD), in agreement with the histological data. The algorithm permitted the classification of the intensities of abnormal signals in sCJD patient FLAIR images with a higher hypersignal in caudate nuclei (10/10) and putamen (6/10) than in thalami. Defining normalized MRI measures of the intensity relations between the internal grey nuclei of patients, we robustly differentiate sCJD and variant CJD (vCJD) patients, in an attempt to create an automatic classification tool of human spongiform encephalopathies.

Algorithms↗
PubMed2005

Survivin expression in ganglioglioma.

Gangliogliomas are unusual central nervous system (CNS) neoplasms occurring mainly in children and young adults and inducing chronic pharmacoresistant epilepsy. These are usually well differentiated neuroepithelial tumors composed of neurons in association with neoplastic glial cells. Gangliogliomas present with favorable outcome. However, some may recur and/or progress to anaplasia and be associated with a dismal prognosis. Since histopathological features do not consistently correlate with clinical outcome, reliable prognostic factors have yet to be defined in gangliogliomas. Survivin is an anti-apoptotic protein whose expression has been found to be of prognostic significance in many human cancers, including gliomas. The objective of this study was to assess survivin expression using immunohistochemistry in 15 gangliogliomas. Ten lesions were low-grade neoplasms whereas 5 were high-grade tumors. Survivin expression appeared restricted to the neoplastic glial component and was detected in 6/15 gangliogliomas. Two additional tumors expressed survivin upon relapse. Half survivin expressing lesions displayed less than 1% immunoreactive cells. Survivin expression in more than 5% neoplastic glial cells was detected only in malignant and/or recurrent gangliogliomas. Extended lifespan in survivin expressing cells might enhance aggressive behavior in these tumors through accumulation of mutations, thereby allowing progression to malignant phenotypes. Survivin expression may carry a negative prognostic value in gangliogliomas.

Adolescent↗
PubMed2005

The N-terminal cleavage of cellular prion protein in the human brain.

Human brain cellular prion protein (PrP(c)) is cleaved within its highly conserved domain at amino acid 110/111/112. This cleavage generates a highly stable C-terminal fragment (C1). We examined the relative abundance of holo- and truncated PrP(c) in human cerebral cortex and we found important inter-individual variations in the proportion of C1. Neither age nor postmortem interval explain the large variability observed in C1 amount. Interestingly, our results show that high levels of C1 are associated with the presence of the active ADAM 10 suggesting this zinc metalloprotease as a candidate for the cleavage of PrP(c) in the human brain.

ADAM Proteins↗
PubMed2005

Enhanced expression of aquaporin 4 in human brain with inflammatory diseases.

Aquaporin 4 (AQP4), one of the water channel proteins on the plasma membrane of astrocytes, is up-regulated in various conditions with brain edema. Possible participation of AQP4 in various inflammatory lesions, more or less associated with edema, was examined in human autopsied brains. Immunohistochemistry was used to investigate AQP4 expression in autopsied brains with multiple sclerosis (MS), human immunodeficiency virus encephalitis (HIVE) or progressive multifocal leukoencephalopathy (PML). The cellular localization of AQP4 and its relation to inflammatory lesions were then examined with double-labeling immunohistochemistry. AQP4 immunoreactivity (IR) was restricted to astrocytes and localized to their entire processes, including their endfeet facing the abluminal surface of capillaries. In MS brains, AQP4-positive astrocytes were more abundant at the periphery of plaques than in their center, as seen in ischemic foci. Quantification of fluorescent signal demonstrated that AQP4 IR was greatly increased around plaques relative to that in unaffected area. Although the white matter was severely involved in HIVE and PML, AQP4-positive astrocytes were rare in the white matter even around perivascular active inflammatory foci. They were abundant in the gray matter and most prominent in the boundary between the gray and white matter, without apparent relation to inflammatory foci. Some bizarre astrocytes in PML exhibited AQP4 IR. Up-regulation of AQP4 was consistently found in astrocytes in various inflammatory lesions. However, the distribution of AQP4-positve astrocytes differed markedly according to disease and was not necessarily related to brain edema, indicating that functions and regulation of AQP4 in human brains are multiple.

AIDS Dementia Complex↗
PubMed2005

Nogo expression in muscle correlates with amyotrophic lateral sclerosis severity.

Nogo, a protein inhibiting axonal regeneration, exhibits a characteristic isoform-specific pattern of expression in skeletal muscle of transgenic mice and patients with amyotrophic lateral sclerosis. Here, the increased levels of Nogo-A or Nogo-B in muscle biopsies of 15 amyotrophic lateral sclerosis patients significantly correlated with the severity of clinical disability and with the degree of muscle fiber atrophy. Nogo-A immunoreactivity was observed selectively in atrophic slow-twitch type I fibers. These results suggest that Nogo expression in muscle is a marker of amyotrophic lateral sclerosis severity.

Adult↗
PubMed2005

Human endogenous retrovirus (HERV)-W ENV and GAG proteins: physiological expression in human brain and pathophysiological modulation in multiple sclerosis lesions.

Antigen expression of a human endogenous retrovirus family, HERV-W, in normal human brain and multiple sclerosis lesions was studied by immunohistochemistry by three independent groups. The HERV-W multicopy family was identified in human DNA from the previously characterized multiple sclerosis-associated retroviral element (MSRV). A panel of antibodies against envelope (ENV) and capsid (GAG) antigens was tested. A physiological expression of GAG proteins in neuronal cells was observed in normal brain, whereas there was a striking accumulation of GAG antigen in axonal structures in demyelinated white matter from patients with MS. Prominent HERV-W GAG expression was also detected in endothelial cells of MS lesions from acute or actively demyelinating cases, a pattern not found in any control. A physiological expression of ENV proteins was detected in microglia in normal brain; however,a specific expression in macrophages was apparently restricted to early MS lesions. Thus, converging results from three groups confirm that GAG and ENV proteins encoded by the HERV-W multicopy gene family are expressed in cells of the central nervous system under normal conditions. Similar to HERV-W7q ENV (Syncitin), which is expressed in placenta and has been shown to have a physiological function in syncytio-trophoblast fusion, HERV-W GAG may thus also have a physiological function in human brain. This expression differs in MS lesions, which may either reflect differential regulation of inherited HERV-W copies, or expression of "infectious" MSRV copies. This is compatible with a pathophysiological role in MS, but also illustrates the ambivalence of such HERV antigens, which can be expressed in cell-specific patterns, under physiological or pathological conditions.

Adult↗
PubMed2005

[Mixed dementia: a neuropathologic point od view].

Alzheimer's disease (AD) and vascular dementia (VaD) are the most frequent causes of dementia in the elderly. Although AD can be diagnosed with a very high degree of accuracy, the distinction between pure AD, VaD and mixed dementia (MD), where both pathologies co-exist in the same patient, remains a controversial issue and one of the most difficult diagnostic challenges. MD represents a very frequent pathology, especially in the elderly, as underlined by the neuropathological studies. However, the respective importance of degenerative and vascular lesions, their interaction in the genesis of dementia and the mere existence of mixed dementia are still debated. Accurate diagnosis of MD is of crucial significance for epidemiologic purposes and for preventive and therapeutic strategies. Until recently, pharmacological studies have generally focused on pure diseases, either AD or VaD, and have provided little data on the best therapeutic approach to MD. This review will provide an overview of neuropathological aspects of MD in the elderly, which appears to be one of the most common forms of dementia.

Aged↗
PubMed2004

Exclusive induction of tau2 epitope in microglia/macrophages in inflammatory lesions-tautwopathy distinct from degenerative tauopathies.

Tau2 antibody recognizes a phosphorylation-independent epitope that is pathologically modified as tau protein is phosphorylated to form neurofibrillary tangles of Alzheimer's disease (AD). Similar modification of tau2 epitope can be induced even in the absence phosphorylation of tau, as we first demonstrated in ischemic foci and in glial cytoplasmic inclusions (GCIs) of multiple system atrophy. This modification of tau2 epitope is distinguishable from those observed in degenerative tauopathies because (1) it is a conformational change, which is reversible upon exposure to a detergent; (2) it shows an absence of fibrils composed of phosphorylated tau protein; and (3) it is characterized by the lack of immunohistochemical labeling by anti-tau antibodies other than tau2. In this study, we expanded this observation to inflammatory foci of different pathologies (human immunodeficiency virus encephalopathy, progressive multifocal leukoencephalopathy or multiple sclerosis) by examining formalin-fixed, paraffin-embedded sections immunostained with a panel of anti-tau antibodies. It was found that tau2 was the only anti-tau antibody that immunolabeled microglia/macrophages in these lesions, and this immunoreactivity was reversibly diminished upon exposure to a detergent. Exclusive apparition of tau2 immunoreactivity in these cells without neurofibrillary pathology may be a secondary event shared with ischemic foci and GCIs. It is, however, related to a unique conformational state of tau, possibly grouped under the name of "tautwopathy", that may represent an initial stage of tau deposition distinct from degenerative tauopathies characterized by fibrils composed of phosphorylated tau protein.

AIDS Dementia Complex↗
PubMed2004

Amyotrophic lateral sclerosis with neuronal intranuclear protein inclusions.

A 46-year-old patient developed amyotrophic lateral sclerosis (ALS) characterized by rapid progression. She needed respiratory assistance after a course of 9 months. She died 4.5 years after onset. Autopsy showed dramatic atrophy of the spinal cord, sparing only the posterior tracts, associated with neuronal loss and astrogliosis in various areas including the anterior horns, motor cortex, striatum, thalamus, and substantia nigra. Ubiquitin immunohistochemistry showed rare skein-like inclusions in the surviving spinal and medullary motor neurons. Eosinophilic inclusions were found in the nuclei of pyramidal neurons in the hippocampus. These inclusions were immunoreactive to antibodies against ubiquitin, promyelocytic leukemia gene product, proteasome, and ataxin-3. They were not immunoreactive to antibodies against tau, cystatin C, neurofilament, alpha-synuclein, SOD-1, and polyglutamine (1C2), and were not stained by ethidium bromide. Similar inclusions were found in the motor cortex. The immunoreactivity of the inclusions was similar to that encountered in diseases associated with CAG repeats, except for the negativity of the immunolabelling with 1C2. At the ultrastructural level, the nuclear inclusions were made of straight filaments (10-12 nm in diameter) arranged at random, reminiscent of the polyglutamine intranuclear hyaline inclusions.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Was the ataxia of Pierre Marie Machado-Joseph disease?: A reappraisal based on the last autopsy case from la Salpêtrière Hospital.

Nosological placement of l'hérédo-ataxie cérébelleuse de Pierre Marie (HAC) has never been established even after several autopsy cases from the original Haudebourg family had been reported. To reappraise the clinical and pathological features of HAC in the current framework of hereditary ataxias, we screened the autopsy records of la Salpêtrière hospital and identified a patient with a diagnosis of HAC who underwent an autopsy in 1943. Clinical features included heredity compatible with autosomal dominant inheritance, spasticity, increased tendon reflexes, mask-like face, visual impairment, nuclear ophthalmoparesis, and exophthalmos in addition to progressive ataxia. Pathological lesions included the spinal cord (spinocerebellar tracts, anterolateral fascicles, and posterior column), cerebellar dentate nucleus, pontine nucleus, pallidum, motor neurons including the oculomotor nucleus, and substantia nigra. The cerebellar cortex and inferior olives were preserved. These clinical and pathological features, similar to those described in patients from the Haudebourg family, a core prototype of HAC, are indistinguishable from those of Machado-Joseph disease. It would then be possible to conclude that some of the patients historically considered to have HAC would today be classified as having Machado-Joseph disease.

Adult↗
PubMed2004

Brain targeting through the autonomous nervous system: lessons from prion diseases.

The human central nervous system (CNS) is targeted by diverse pathogens that use distinct pathways to bypass the blood-brain barrier, such as trafficking into the brain via infected blood cells or using retrograde axonal transport through sensory or motor fibers. Prions are transmissible agents that induce a devastating subacute neurodegeneration when they successfully reach the CNS. Two recent studies focusing on pathways of prion neuroinvasion provide converging evidence that, in the case of peripheral transmission, such as human consumption of contaminated tissue, the infectious agent uses the sympathetic noradrenergic neurons to reach the CNS after early replication in lymphoid tissues.

Adrenergic Fibers↗
PubMed2003

The sympathetic nervous system is involved in variant Creutzfeldt-Jakob disease.

Prion epizoonoses spread from animals consumed by humans raise the question of which pathways lead to prion neuroinvasion after oral exposure of humans. Here we show that neurons of sympathetic ganglia of patients with variant Creutzfeldt-Jakob disease (vCJD) accumulate the abnormal isoform of the protein prion. This observation shows the involvement of the sympathetic nervous system in the pathogenesis of vCJD and suggests a role for GUT-associated sympathetic neurons in prion propagation in humans after oral contamination.

Adult↗