Alzheimer Disease: Hauw JJ

Forette F, Hauw JJ. · Université Paris V, Hôpital Broca, Fondation nationale de Gérontologie, International Longevity Center (ILC)-France. · Bull Acad Natl Med. · Pubmed #18819689 No free full text.

Abstract: We review the main therapeutic targets in Alzheimer's disease. Current treatments include cholinesterase inhibitors and the glutamate-modulating drug memantin. Other neurotransmitters such as serotonin, histamine and noradrenaline may also be targeted. Although useful, however, these symptomatic treatments do not prevent neuronal degeneration and death. Epidemiological studies suggest that treatments given for other reasons, such as antiinflammatory agents (including NSAIDs), cholesterol-lowering drugs, hormone replacement therapy and antioxidants, may prevent or improve Alzheimer-type dementia, but this is not always borne out in controlled clinical trials. Prevention of hypertension significantly reduces the incidence of vascular dementia and of Alzheimer-type dementia, albeit through an unknown mechanism. Alzheimer's disease is characterized by two main lesions: amyloid plaques and neurofibrillary tangles composed of aggregated A Beta peptides and hyperphosphorylated tau. Active and passive immunization against A beta has given promising results. Other exciting approaches include modulation of A beta processing by inhibiting BACE1 or gamma-secretase or upregulating alpha-secretase; A beta peptide catabolism; inhibition of beta fibrillization; and reducing tau phosphorylation or inhibiting tau aggregation. More remote possibilities include gene therapy and the use of growth factors to increase neurogenesis.

Zekry D, Duyckaerts C, Hauw JJ. · Laboratoire de neuropathologie Raymond Escourolle, Hôpital de la Salpêtrière, Paris (75). · Presse Med. · Pubmed #17553655 No free full text.

Abstract: The concept of vascular dementia has evolved over the past century to include multiple underlying pathophysiological mechanisms. Neuroimaging techniques offer new and better ways to identify the presence of cerebrovascular pathology, although they do not improve our ability to link these changes to the onset of clinical cognitive impairment. Clinical criteria for vascular dementia have also evolved but they remain imperfect. Most epidemiological studies define mixed dementia as the coexistence of Alzheimer's disease and vascular dementia. Clinicopathologic correlations show a clear association between the concomitant presence of vascular and Alzheimer lesions and the severity of cognitive impairment in mixed dementia and provide strong support for the validity of the mixed dementia concept. Mixed dementia is a very frequent disease that remains underdiagnosed, especially in the elderly. The diagnosis of vascular and mixed dementia remains a clinical challenge and cannot be improved without further studies of clinicopathological correlations and functional neuroimaging. Preventive therapeutic interventions include control of vascular risk factors and especially treatment of hypertension.

Zekry D, Duyckaerts C, Hauw JJ. · Laboratoire de neuropathologie, Hôpital de la Salpêtrière, Paris, France. · Psychol Neuropsychiatr Vieil. · Pubmed #16316816 No free full text.

Abstract: 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.

Duyckaerts C, Hauw JJ. · Laboratoire de Neuropathologie Raymond Escourolle, Groupe Hospitalier Pitié-Salpêtrière, 75651 Paris. · Bull Acad Natl Med. · Pubmed #14556441 No free full text.

Abstract: The Lewy body, an eosinophilic inclusion around 10 microns in diameter, is localised in the neuronal perikaryon. Its dense core is surrounded by a clear halo, which is lacking in the so-called "cortical Lewy bodies". Numerous proteins have been identified in Lewy bodies, among which the three neurofilament isoforms, ubiquitin and proteasome subunits. More recently, alpha-synuclein--a pre-synaptic protein--has been found to be the essential constituent of the Lewy body. Alpha-synuclein antibody has greatly increased the sensitivity of the neuropathological examination: it has emphasized the frequency of "Lewy neurites" (accumulation of alpha--synuclein in neuronal processes) and has shown the importance of extra-nigral pathology. Lewy bodies and neurites are indeed to be found in many areas of the central and peripheral nervous system: stellate ganglia, cardiac and enteric plexus, pigmented nuclei of the brainstem, basal nucleus of Meynert, amygdala, limbic nuclei of the thalamus, parahippocampal and cingulate gyri, insula and isocortex. Lewy body diseases include at least three clinical syndromes: 1) idiopathic Parkinson disease in which the brainstem bears the brunt of the pathology 2) Parkinson disease dementia in which Lewy lesions are found in the brainstem and are also abundant in the isocortex. A large number of senile plaques is frequently associated. 3) In dementia with Lewy bodies, the same lesions are observed but the cognitive deficit occurs first or shortly (less than one year) after the motor symptoms.

Hauw JJ, Duyckaerts C. · Université Paris-6, Académie de médecine, Raymond-Escourolle Neuropathology Laboratory, centre hospitalo-universitaire Pitié-Salpêtrière, Paris, France. · C R Biol. · Pubmed #12365416 No free full text.

Abstract: The prevalence of dementia dramatically increases during ageing, and this puts a serious strain on the optimism brought by the continuous increase in life expectancy observed in most industrialised countries. Diseases that produce dementia are numerous, and the cognitive deficit results from lesions of various regions and from different mechanisms. This modulates the possible prediction, prevention and cure of dementia. Emphasis is put on the necessity of, and prerequisite for, efficient research in the field of dementia. Three paradigmatic dementing disorders are reviewed. Subacute spongiform encephalopathies (prion diseases) constitute a biological enigma and a public health concern. In Alzheimer's disease and vascular or mixed dementia, the clinical diagnosis is still imperfect, and this hinders research. Distinguishing and accurately identifying the various types of dementia is essential for understanding their mechanism and for developing efficient therapeutic strategies, preventive and curative. For such objectives, the study of human brain tissue will remain mandatory until non-invasive markers and additional models are available. Ethical reasons banish the use of cerebral biopsy and favour the promotion of autopsy.

Zekry D, Hauw JJ, Gold G. · Hôpitaux Universitaires de Genève, Thônex, Switzerland. · J Am Geriatr Soc. · Pubmed #12165002 No free full text.

Abstract: Alzheimer's disease (AD) and vascular dementia (VaD) are the most frequent causes of dementia in older people. Although AD can be diagnosed with a considerable degree of accuracy, the distinction between isolated AD, VaD, and mixed dementia (MD), where both pathologies coexist in the same patient, remains a controversial issue and one of the most difficult diagnostic challenges. Although MD represents a very frequent pathology, especially in older people, as reported in neuropathological studies, the respective importance of degenerative and vascular lesions, their interaction in the genesis of dementia, and the mere existence of MD are still debated. Accurate diagnosis of MD is of crucial significance for epidemiological purposes and for preventive and therapeutic strategies. Until recently, pharmacological studies have generally focused on pure disease, AD or VaD, and have provided little information on the best therapeutic approach to MD. This article provides an overview of MD in older people. A retrospective review of the recent literature on prevalence, incidence, course, risk factors, diagnosis, and treatment of MD was performed. The article also emphasizes the need for further studies, including neuropsychological and functional evaluations, and neuroimaging and clinicopathological correlations to develop a better understanding of MD, which appears to be one of the most common forms of dementia.

Hauw JJ, Escourolle F, Colle MA, Duyckaerts C. · Laboratoire de Neuropathologie R. Escourolle, Hôpital de La Salpétrière, Université Pierre et Marie Curie, Association Claude Bernard, INSERM U360. · Ann Pathol. · Pubmed #11084412 No free full text.

This publication has no abstract.

Duyckaerts C, Colle MA, Delatour B, Hauw JJ. · Laboratoire de Neuropathologie R. Escourolle, Hôpital de La Salpêtrière, Paris. · Rev Neurol (Paris). · Pubmed #10637934 No free full text.

Abstract: Alzheimer disease appears to be a stereotyped mode of reaction of the central nervous system to various types of aggression such as different mutations involving various proteins, trisomy 21 or repeated head trauma as in dementia pugilistica. Rather than a disease, it appears to be a clinicopathological syndrome due to various causes. Lesions may be considered under 3 headings: neurofibrillary pathology, A beta peptide deposits and loss (neuronal and synaptic). Neurofibrillary pathology includes the neurofibrillary tangle, the crown of the senile plaque and the neuropil threads. All those lesions are characterized by the same ultrastructure--i.e. the accumulation of paired helical filaments--and the same immunohistochemistry: they are labelled by antibodies directed against the tau proteins. The amyloid deposits, present in the core of the senile plaque and in the vascular walls, are made of a 40 to 42 amino-acids long peptide, named A beta, derived from the amyloid precursor protein (APP). Antibodies directed against the A beta peptide also label diffuse deposits that are devoid of the tinctorial affinities and of the biochemical properties of amyloid substances. Those diffuse deposits are insufficient to cause dementia since they may be observed in high density in aged people without intellectual deterioration. Neuronal loss occurs after neurofibrillary pathology. The role of the synaptic pathology remains discussed. Besides tau proteins, A beta peptide and APP, several other proteins may play an important role: apolipoprotein E which could act as a chaperone protein, inducing or facilitating the formation of amyloid, presenilins 1 and 2, mutated in some cases of familial Alzheimer disease, alpha-synuclein which is present in the Lewy bodies found in Parkinson disease and in dementia with Lewy bodies. The A beta deposits are diffusely distributed in the cerebral cortex; the neurofibrillary changes have a hierarchical distribution. The progression of the neurofibrillary pathology in the various cortical areas follow a stereotyped sequence that may help to grade the severity of the disease. Progression may take decades. The relations between aging and Alzheimer disease are still poorly understood. Frequency of Alzheimer type lesions in old people could suggest that they are the inevitable burden of age, but this has been discussed.

Liberski PP, Sikorska B, Hauw JJ, Kopp N, Streichenberger N, Giraud P, Budka H, Boellaard JW, Brown P. · Department of Molecular Pathology and Neuropathology, Medical University of Lodz, PL 92-216 Lodz, Poland. · Virus Res. · Pubmed #18164506 No free full text.

Abstract: Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS) and Fatal Familial Insomnia (FFI) are slow neurodegenerative disorders classified as transmissible spongiform encephalopathies (TSEs) or prion diseases, which appear in sporadic, hereditary or environmentally acquired forms. Tubulovesicular structures (TVS) are ultrastructural particles of unknown origin and chemical composition found in the brains of both animal and human forms of transmissible spongiform encephalopathies or prion diseases. In this paper, we report the results of a search for TVS in a total of 13 cases of sporadic Creutzfeldt-Jakob disease, three cases of Gerstmann-Sträussler-Scheinker disease, two cases of Fatal Familial Insomnia, and individual cases of familial, iatrogenic, and variant CJD (vCJD). TVS were found in all but one sporadic and one familial case of CJD. As controls, we examined 15 cases of Alzheimer's disease (AD), two cases of Pick's disease, and one case of multiple system atrophy. TVS were not present in any of these cases. This study confirms the TSE-specificity of TVS, the morphology of which suggests a possible pathogenetic role and relationship to recently described virion-like arrays of 25nm particles in scrapie-infected tissue cultures.

Privat N, Laffont-Proust I, Faucheux BA, Sazdovitch V, Frobert Y, Laplanche JL, Grassi J, Hauw JJ, Haïk S. · INSERM, Avenir Team-Human Prion Diseases, Paris, France. · Mod Pathol. · Pubmed #18084251 links to  free full text

Abstract: Demonstration of pathological prion protein accumulation in the central nervous system is required to establish the diagnosis of transmissible subacute encephalopathies. In humans, this is frequently achieved using prion protein immunohistochemistry in paraffin-embedded tissue, a technique that requires multiple epitope retrieval and denaturing pretreatments. In addition to being time-consuming, this procedure induces tissue alterations that preclude accurate morphological examination. The aim of this study was to simplify prion protein immunohistochemistry procedure in human tissue, together with increased sensitivity and specificity. We screened a panel of 50 monoclonal antibodies produced using various immunogens (human and ovine recombinant prion protein, prion protein peptides, denatured scrapie-associated fibrils from 263K-infected Syrian hamsters) and directed against different epitopes along the human prion protein sequence. A panel of different forms of genetic, infectious and sporadic transmissible subacute encephalopathies was assessed. The monoclonal 12F10 antibody provided a high specificity and fast immunodiagnosis with very limited denaturing pretreatments. A standardized and reliable fast immunostaining procedure was established using an automated diagnostic system (Nexes, Ventana Medical Systems) and allowed prion protein detection in the central nervous system and in tonsil biopsies. It was evaluated in a series of 300 patients with a suspected diagnosis of transmissible subacute encephalopathies and showed high sensitivity and specificity.

Bensemain F, Hot D, Ferreira S, Dumont J, Bombois S, Maurage CA, Huot L, Hermant X, Levillain E, Hubans C, Hansmannel F, Chapuis J, Hauw JJ, Schraen S, Lemoine Y, Buée L, Berr C, Mann D, Pasquier F, Amouyel P, Lambert JC. · INSERM, U744, Institut Pasteur de Lille, Université de Lille 2, Lille, France. · Mol Psychiatry. · Pubmed #17893704 No free full text.

Abstract: To more rapidly identify candidate genes located within chromosomal regions of interest defined by genome scan studies in Alzheimer's disease (AD), we have developed a customized microarray containing all the ORFs (n=2741) located within nine of these regions. Levels of gene expression were assessed in total RNA from brain tissue of 12 controls and 12 AD patients. Of all genes showing differential expression, we focused on the ornithine transcarbamylase (OTC) gene on Xp21.1., a key enzyme of the urea cycle which we found to be expressed in AD brains but not in controls, as confirmed by RT-PCR. We also detected mRNA expression of all the other urea cycle enzymes in AD brains. Immunochemistry experiments revealed that the OTC expression was strictly restricted to vascular endothelial cells in brain. Furthermore, OTC activity was 880% increased in the CSF of probable AD cases compared with controls. We analysed the association of the OTC -389 G/A and -241 A/G promoter polymorphisms with the risk of developing AD. We observed that rare haplotypes may be associated with the risk of AD through a possible modulation of the methylation of the OTC promoter. In conclusion, our results suggest the involvement of a new pathway in AD brains involving the urea cycle.

Vital A, Canron MH, Gil R, Hauw JJ, Vital C. · Neuropathology Department, Victor Segalen-Bordeaux 2 University, Bordeaux, France. · Neuropathology. · Pubmed #17645242 No free full text.

Abstract: Neurodegenerative disorders are characterized by the correlation of clinical symptoms and neuropathological changes in the brain. However, overlaps between distinct entities are becoming more and more evident. We report the coexistence of Alzheimer pathology and alpha-synuclein inclusions in a sporadic, methioninelvaline type 1, Creutzfeldt-Jakob disease (CJD) case. There were neurofibrillary changes in the neocortex and beta amyloid cerebral angiopathy was marked. Several Lewy bodies were present in the substantia nigra, locus ceruleus and the dorsal motor nucleus of the vagus, and alpha-synuclein cytoplasmic inclusions were also found in cortical neurons. These findings raise the debated relationship between Parkinson's disease with dementia, dementia with Lewy bodies and a Lewy body variant of Alzheimer disease. Among the factors that may have contributed to this considerable morphological overlap are the patient's age (79 years at autopsy) and the over 2-year duration of the disease. As the average disease duration in sporadic methionine/valine type 1 CJD is less than 6 months, it seems legitimate to speculate that the initial symptoms resulted from Alzheimer and alpha-synuclein related pathologies. This observation shows that CJD can be present in elderly patients who are suspected of having other neurodegenerative diseases, which could underline the importance of neuropathology-based surveillance systems.

Giaccone G, Mangieri M, Capobianco R, Limido L, Hauw JJ, Haïk S, Fociani P, Bugiani O, Tagliavini F. · Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy. · Neurobiol Aging. · Pubmed #17560687 No free full text.

Abstract: Cerebral accumulation of hyperphosphorylated tau (phospho-tau) occurs in several neurodegenerative conditions including Alzheimer disease. In prion diseases, phospho-tau deposition has been described in a rare genetic form, Gerstmann-Sträussler-Scheinker disease, but is not considered part of the neuropathological picture of Creutzfeldt-Jakob disease. Aim of this study was to investigate whether changes related to phospho-tau accumulation are present in the brain of patients with variant Creutzfeldt-Jakob disease (vCJD) that shares with Gerstmann-Sträussler-Scheinker disease abundant prion protein (PrP) deposition in amyloid form. The analysis was extended to experimental mouse models of vCJD. We detected a large number of phospho-tau-immunoreactive neuritic profiles, often clustered around PrP amyloid deposits, not only in the cerebral cortex, but also in the cerebellum of all vCJD patients examined, in the absence of Abeta. Although less constantly, phospho-tau was localized in some perikaria and dendrites. The biochemical counterpart was the presence of phospho-tau in the detergent-insoluble fraction of cerebral cortex. Phospho-tau-immunoreactive neuronal profiles were also found in association with PrP deposits in mouse models of vCJD. These findings suggest that the abnormal forms of PrP associated with vCJD trigger a tauopathy, and provide a paradigm for the early stages of tau pathology associated with cerebral amyloidoses, including Alzheimer disease.

Alafuzoff I, Pikkarainen M, Al-Sarraj S, Arzberger T, Bell J, Bodi I, Bogdanovic N, Budka H, Bugiani O, Ferrer I, Gelpi E, Giaccone G, Graeber MB, Hauw JJ, Kamphorst W, King A, Kopp N, Korkolopoulou P, Kovács GG, Meyronet D, Parchi P, Patsouris E, Preusser M, Ravid R, Roggendorf W, Seilhean D, Streichenberger N, Thal DR, Kretzschmar H. · Department of Neuroscience and Neurology, Kuopio University, Kuopio University Hospital, Finland. · J Neuropathol Exp Neurol. · Pubmed #16896308 No free full text.

Abstract: 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.

Portet F, Dauvilliers Y, Campion D, Raux G, Hauw JJ, Lyon-Caen O, Camu W, Touchon J. · UNCD, Gui de Chauliac Hospital, Montpellier, France. · Neurology. · Pubmed #14581682 No free full text.

Abstract: The authors describe a 28-year-old woman with histopathologically confirmed early onset Alzheimer disease characterized by severe frontal lobe involvement associated with a de novo mutation in the presenilin 1 gene (PSEN1).

Girardot N, Allinquant B, Langui D, Laquerrière A, Dubois B, Hauw JJ, Duyckaerts C. · Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière, AP-HP & Association Claude Bernard, Paris, Inserm U106, Paris, France. · Neuropathol Appl Neurobiol. · Pubmed #14507337 No free full text.

Abstract: The protein flotillin-1 is associated with the 'lipid rafts', that is, membrane microdomains that are enriched in cholesterol and sphingolipids. We compared flotillin-1 immunoreactivity in the hippocampus, amygdala and isocortex (Brodmann area 22) of six controls and 13 Alzheimer's disease (AD) cases (10 sporadic and three familial). A diffuse labelling of the neuropil was observed in most of the samples. The intensity of this labelling was not correlated with the density of neurofibrillary tangles (NFT) or of senile plaques. Some neuronal cell bodies were diffusely labelled in patients as in controls. Immunostained granular bodies were found in the cell body of a few neurones. The density of neuronal profiles containing large granular bodies (diameter > or =2 microm) was significantly higher in AD cases and was correlated with the density of NFTs in the three regions that were studied. Sections stained by double immunofluorescence methods and examined with confocal microscopy suggested that flotillin-1 accumulated most often in tangle-bearing neurones (76% of flotillin-1-positive neurones contained a NFT). Flotillin-1 immunoreactivity, even when found in a tangle-bearing neurone, was not colocalized with tau protein indicating that the two proteins were not in close contact and probably in different subcellular compartments. Flotillin-1-positive granular bodies were also found in neurones containing Pin1-positive vesicles but were not colocalized with them. Flotillin-1 immunoreactivity was colocalized with cathepsin D, a lysosomal marker. These data indicate that flotillin-1, a marker of rafts, accumulates in lysosomes of tangle-bearing neurones in the course of AD.

Zekry D, Duyckaerts C, Belmin J, Geoffre C, Moulias R, Hauw JJ. · Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la Salpêtrière, INSERM U 106 and 360, Association Claude Bernard, Pierre et Marie Curie University, 47 Bd de l'Hôpital, 75013 Paris, France. · Acta Neuropathol. · Pubmed #12898153 No free full text.

Abstract: Abeta peptide deposits are observed in brain cortical and leptomeningeal microvessels in a few families, in patients with Alzheimer's disease and in cognitively normal elderly subjects. These deposits, which cause Abeta amyloid angiopathy, are usually associated with other lesions induced by Abeta peptide and tau pathologies. To investigate the consequences of cerebral amyloid angiopathy on arterial morphology and search for correlations with the degree of cognitive impairment, we carried out a prospective clinicopathological and morphometric study in 29 institutionalized elderly patients cognitively normal or affected with sporadic dementia associated with Alzheimer-type lesions, cerebral infarcts or both. We measured the external and internal diameters of arteries 40-120 microm wide, containing moderate or severe Abeta deposits, and of unaffected arteries in the temporal and frontal lobes. We found no differences in the mean external diameters. In contrast, the mean internal diameters of vessels with moderate Abeta deposits were smaller than those of unaffected vessels. Conversely, the internal diameters of severely affected vessels were larger than those of unaffected vessels. This suggests that arterial walls become thicker during the early stages of amyloid angiopathy, and the diameter of the lumen decreases, whereas during advanced stages, the walls become thinner and the lumen becomes larger. In addition, we assessed the overall severity of amyloid angiopathy. This showed that thinner arterial walls and the severity of amyloid angiopathy were correlated to dementia. In a multivariate model that integrates the other macroscopic and microscopic lesions that may be implied in the mechanism of cognitive impairment, the severity of amyloid angiopathy per se explained 10% of the variability in the cognitive impairment.

Metsaars WP, Hauw JJ, van Welsem ME, Duyckaerts C. · Laboratoire de Neuropathologie R. Escourolle, Hôpital de La Salpêtrière, 47, Boulevard de l'Hôpital, Cedex 13 75651, Paris, France. · Neurobiol Aging. · Pubmed #12714113 No free full text.

Abstract: Progression of neuritic and Abeta pathology in the cerebral cortex during aging and Alzheimer disease is well known, but the chronology of the various types of lesions (Abeta deposition, amyloid formation, inflammation, ubiquitination, tangle formation) within a given area has not been fully elucidated. We examined these lesions in the primary visual cortex (Brodmann area 17), correlating them with the severity of the disease (as evaluated by the cognitive status and the number of cortical samples that contained neurofibrillary tangles). Four 'grades' were identified. At grade 1, only deposits of Abeta peptide were noticed. At grade 2, Congo red positive deposits, and processes containing ubiquitin and cathepsin D immunoreactivity around plaque cores could also be found. At grade 3, neuritic plaques and neuropil threads were present, and at grade 4, neurofibrillary tangles. The density of all the lesions dramatically increased at grade 4. The sequence of isocortical lesions from grade 1 to grade 4 is compatible with a cascade of events beginning with deposition of Abeta peptide and ending with neurofibrillary tangle.

Rangon CM, Haïk S, Faucheux BA, Metz-Boutigue MH, Fierville F, Fuchs JP, Hauw JJ, Aunis D. · INSERM Unité 338, 5 rue Blaise Pascal, 67084 Strasbourg Cedex, France. · Neuroreport. · Pubmed #12692477 No free full text.

Abstract: Brain lesions in Creutzfeldt-Jakob disease (CJD) include spongiform change, neuronal loss, amyloid plaques, astrogliosis and microglial activation. Microglia are thought to play a key role in prion-induced neurodegeneration. However, the intermediate molecules supporting relationships between neurons and microglia are still unknown. Chromogranins (Cg) are soluble glycophosphoproteins that can activate microglial cells leading to a neurotoxic phenotype. The immunoreactive patterns of CgA and CgB were investigated in CJD and compared to those observed in Alzheimer's disease. We found that CgB, but not CgA, immunoreactivity was selectively associated with prion protein deposits, whereas CgA was only seen in Abeta plaques. This suggests a specific influence of the constitutive amyloid protein on chromogranin secretion and a role of CgB in the CJD neurodegenerative process.

Hauw JJ, Zekry D, Seilhean D, Forette B, Gallinari C, Laurent M, Moulias R, Piette F, Sachet A, Duyckaerts C. · Laboratoire de Neuropathologie R. Escourolle, INSERM U 106 et 360, Association Claude Bernard, Groupe Hospitalier Pitié-Salpêtrière, 47-83 boulevard de l'Hôpital, 75651 Paris. · J Mal Vasc. · Pubmed #12587216 No free full text.

Abstract: 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.

Maurage CA, Sergeant N, Ruchoux MM, Hauw JJ, Delacourte A. · Department of Neuropathology, CHRU, 59037 Lille, France. · Acta Neuropathol. · Pubmed #12536218 No free full text.

Abstract: Microtubule-associated protein tau is abnormally phosphorylated in many neurodegenerative disorders, and is the major component of neurofibrillary degeneration, a degenerating process with many biochemical phenotypes. The serine 199 (S199) residue of tau is phosphorylated at early and late stages of Alzheimer's disease (AD). We studied the immunohistochemical distribution of this phosphorylated epitope in AD and other neurodegenerative disorders, as well as in controls of different ages. The phosphorylated S199 (S199P) epitope was observed in tau lesions from numerous diseases with neurofibrillary degeneration. This epitope was found to be abundantly expressed in the hippocampus formation in childhood and in young adult brain samples, and more specifically in subsets of neurons vulnerable to neurodegeneration. Interestingly, our data suggests that S199P is particularly resistant to phosphatase activity occurring during post-mortem delays. We suggest a peculiar and important role of the S199 residue as a qualitative indicator of the normal and pathological phosphorylation status of tau proteins.

Zekry D, Duyckaerts C, Belmin J, Geoffre C, Herrmann F, Moulias R, Hauw JJ. · Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la Salpêtrière, INSERM U 106 and 360, Association Claude Bernard, Pierre et Marie Curie University, Paris, France. · Neurobiol Aging. · Pubmed #12498955 No free full text.

Abstract: Vascular dementia appears rarer than previously thought, but the contribution of vascular lesions to cognitive impairment in Alzheimer's disease (AD) affected patients (mixed dementias) is now recognized as frequent. The role of strategic areas of the brain involved in the cognitive decline induced by vascular lesions and their relative contributions to the severity of the dementing process remain poorly understood. We determined the relationship between the severity of clinical dementia and the volume of different brain areas affected by infarcts in a prospective clinicopathological study in elderly patients. A volumetric study of the functional zones of Mesulam's human brain map affected by vascular lesions was made and correlations between quantified neuropathological data and the severity of dementia were performed in cases with large vascular lesions only, pure AD, and both lesions. The severity of cognitive impairment was significantly correlated with the total volume of infarcts but in a multi-variate model the volume destroyed in the limbic and heteromodal association areas, including the frontal cortex and in the white matter explained 50% of the variability in MMSE and GDS. The total volume of ischemic lesions explained only 0.1-5% of the variability in MMSE and GDS. Age only explained an extra of 0.1-1.6%. This study confirms that infarcts located in strategic areas have a role in the mechanism of cognitive impairment and brings a key for their quantification. It may be useful for developing neuropathological criteria in multi-infarct and mixed dementias.

Zekry D, Duyckaerts C, Belmin J, Geoffre C, Moulias R, Hauw JJ. · Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la Salpêtrière, 47-83, Bd de l'Hôpital, 75651, Paris, Cedex 13, France. · J Neurol. · Pubmed #12420093 No free full text.

Abstract: Clarifying the etiology of dementia is one of the most difficult diagnostic challenges, especially in the elderly. We examined the accuracy of clinical criteria to distinguish Alzheimer's disease (AD) and dementia associated with infarcts of the brain, either isolated (vascular dementia) or associated with degenerative lesions (mixed dementia). We carried out a prospective clinico-neuropathological study in a selected series of hospitalized patients. We evaluated the clinical aspects of 33 patients aged over 75 years by use of the criteria and scores of DSMIII, NINCDS-ADRDA, Loeb and Gandolfo, ADDTC and NINDS-AIREN and the Hachinski Ischemic Score. The neuropathological diagnosis was considered to be the gold standard. When comparing clinical criteria and neuropathology, the agreement was moderate for Hachinski's score (0.50) and Loeb's score (0.43) and substantial for the ADDTC (0.63) and the NINDS-AIREN (0.67). When mixed dementias were excluded, the agreement between all clinical criteria and scores and the pathological diagnosis rose to 0.88. Hachinski's score was the most sensitive (0.89) and the NINDS-AIREN the most specific (0.86) for the diagnosis of vascular dementia. In conclusion, all sets of clinical criteria distinguished pure AD from vascular dementia with a high accuracy whereas mixed dementia was clinically under-recognized. The NINDS-AIREN criteria were the most discriminating for the accurate identification of patients with mixed dementia.

Zekry D, Duyckaerts C, Moulias R, Belmin J, Geoffre C, Herrmann F, Hauw JJ. · Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la Salpêtrière, INSERM U 106 and 360, Association Claude Bernard, Pierre et Marie Curie University, 47 Bd de l'Hôpital, 75013 Paris, France. · Acta Neuropathol. · Pubmed #11935264 No free full text.

Abstract: The relative importance of vascular and Alzheimer's disease (AD) lesions, their interaction in the development of cognitive impairment and the very existence of mixed dementia induced by the potentiation of both mechanisms remain controversial. The aim of this study was to assess whether the patients with infarcts and lacunes have fewer plaques and tangles than those without vascular lesions, for similar severity of clinical dementia. We performed a prospective clinicopathological study in elderly patients of a long-stay care unit. The severity of clinical dementia was assessed by psychometry performed according to standardized methods less than 6 months before death. A volumetric study of cerebral vascular lesions was performed at post-mortem study of the brain. The density of neuritic plaques (SP), Amyloid beta focal deposits (A beta FD), and neurofibrillary tangles (NFT) in the temporal and frontal isocortex was quantified. According to DSM III criteria, 28 of the 33 patients for whom autopsies were performed had dementia. Twenty-four of the included patients had degenerative or vascular lesions, or both. The volume of infarcts and lacunes was significantly correlated with the severity of cognitive impairment. The density of SP, A beta FD and NFT in the temporal and frontal isocortex was significantly lower when vascular lesions were present. For similar clinical severity of dementia, there were fewer AD lesions in patients with vascular lesions than in those without vascular lesions.

Hauw JJ. · Laboratoire de neuropathologie Raymond-Escourolle, Groupe hospitalier La Pitié-La Salpêtrière, Université Pierre-et-Marie-Curie, Paris-VI, INSERM Unité 360, Association Claude-Bernard, 75651 Paris. · Rev Prat. · Pubmed #11828629 No free full text.

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