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Biomedical subjects

Jean-Jacques Hauw

Publications and source records attributed to Jean-Jacques Hauw.

At least 37 records · Page 2Linked to original sources
PubMed2003

Cerebral amyloid angiopathy in the elderly: vessel walls changes and relationship with dementia.

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.

Aged↗
PubMed2003

Different chromogranin immunoreactivity between prion and a-beta amyloid plaque.

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.

Adult↗
PubMed2003

Polymorphism of the codon 129 of the prion protein (PrP) gene and neuropathology of cerebral ageing.

We studied whether codon 129 polymorphism of the PrP gene modulates the presence of tau- and Abeta-associated lesions among 188 patients over 70 years of age without evidence of dementia. Val allele carriers, either heterozygotes or homozygotes, were more frequently affected by Abeta-associated lesions than non Val allele carriers, whereas there were no differences for tau-positive neurones. Val allele carriers also had more focal and diffuse Abeta deposits. This association was most significant in the highest Braak's stages for neurofibrillary tangles (>/=III). In this group, cases with at least one Val allele had nearly twice as many Abeta-associated lesions. The most affected areas were the entorhinal cortex, TF-TH and the superior temporal cortex, where odds ratios for focal Abeta deposits ranged from 3.5 to 4.6.

Aged↗
PubMed2003

Parkinson's disease, subthalamic stimulation, and selection of candidates: a pathological study.

We report on a patient with Parkinson's disease (PD) who was moderately improved by stimulation of the subthalamic nucleus (STN) and died 2 years after electrode implantation. After neurosurgery, symptoms that had responded to levodopa treatment preoperatively continued to improve. Postural instability, dysarthria, and cognitive impairment continued to worsen, despite STN stimulation and levodopa treatment. Postmortem examination of the brain confirmed the diagnosis of PD and showed that the electrodes had been correctly positioned within the STN. The failure of STN stimulation in this patient confirms the importance of screening and excluding patients from surgery with evolving parkinsonian axial symptoms or cognitive impairment.

Aged↗
PubMed2003

Neuromelanin associated redox-active iron is increased in the substantia nigra of patients with Parkinson's disease.

Degeneration of dopaminergic neurones during Parkinson's disease is most extensive in the subpopulation of melanized-neurones located in the substantia nigra pars compacta. Neuromelanin is a dark pigment produced in the dopaminergic neurones of the human substantia nigra and has the ability to bind a variety of metal ions, especially iron. Post-mortem analyses of the human brain have established that oxidative stress and iron content are enhanced in association with neuronal death. As redox-active iron (free Fe2+ form) and other transition metals have the ability to generate highly reactive hydroxyl radicals by a catalytic process, we investigated the redox activity of neuromelanin (NM)-aggregates in a group of parkinsonian patients, who presented a statistically significant reduction (- 70%) in the number of melanized-neurones and an increased non-heme (Fe3+) iron content as compared with a group of matched-control subjects. The level of redox activity detected in neuromelanin-aggregates was significantly increased (+ 69%) in parkinsonian patients and was highest in patients with the most severe neuronal loss. This change was not observed in tissue in the immediate vicinity of melanized-neurones. A possible consequence of an overloading of neuromelanin with redox-active elements is an increased contribution to oxidative stress and intraneuronal damage in patients with Parkinson's disease.

Aged↗
PubMed2003

[Lewy bodies, a misleading marker for Parkinson's disease?].

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.

Aging↗
PubMed2002

Phosphorylated serine 199 of microtubule-associated protein tau is a neuronal epitope abundantly expressed in youth and an early marker of tau pathology.

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.

Adolescent↗
PubMed2002

Degenerative and vascular lesions of the brain have synergistic effects in dementia of the elderly.

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.

Aged↗
PubMed2002

Severe demyelinating myelopathy with low human T cell lymphotropic virus type 1 expression after transfusion in an immunosuppressed patient.

We describe an immunosuppressed patient who developed myelopathy after transfusion with human T cell lymphotropic virus type 1-infected blood products during cardiac transplantation; immunoglobulins and fibrinogen deposition indicated disruption of the blood-brain barrier. The low degree of inflammation and virus expression suggests that demyelination may have been caused by an antibody- and complement-mediated process and by an alteration of the spinal cord microenvironment with activation of microglial cells and astrocytes.

Adult↗
PubMed2002

Alzheimer's disease and brain infarcts in the elderly. Agreement with neuropathology.

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.

Aged↗
PubMed2002

Dementia, the fate of brain? Neuropathological point of view.

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.

Aging↗
PubMed2002

Metabolic changes in the basal ganglia of patients with Huntington's disease: an in situ hybridization study of cytochrome oxidase subunit I mRNA.

On the basis of the functional model of the basal ganglia developed in the 1980s and the neuropathological findings in Huntington's disease (HD), changes in the neuronal activity of the basal ganglia have previously been proposed to explain the abnormal movements observed in this pathology. In particular, it has been stated that the neurodegenerative process affecting the basal ganglia in the disease should provoke a hypoactivity in the internal segment of the pallidum (GPi) that could explain choreic movements observed in the disease. To test this functional hypothesis, we performed an in situ hybridization study on control and HD brains postmortem, taking cytochrome oxidase subunit I (COI) mRNAs expression as index of neuronal activity. As most of the HD patients studied were under chronic neuroleptic (NL) treatment, we also studied the brains of non-HD patients under chronic NL treatment. Our results show that in HD brain the number of neurons expressing COI mRNA tends to be lower in the striatum, GPe and GPi, suggesting a severe involvement of these structures during the neurodegenerative process. Moreover, COI mRNA level of expression was markedly reduced within neurons of the putamen and GPe. Surprisingly, COI mRNA expression was not modified in the GPi in HD brains compared with controls. This paradoxical result in the GPi may be explained by the antagonistic effect of GPe hypoactivity and the degenerative process involving neurons of GPi. Our results indicate that the functional modifications, and consequently the pathophysiology of abnormal movements, observed in HD basal ganglia are more complex than expected from the currently accepted model of the basal ganglia organization.

Adult↗
PubMed2002

Lack of up-regulation of ferritin is associated with sustained iron regulatory protein-1 binding activity in the substantia nigra of patients with Parkinson's disease.

Dopaminergic neurones degenerate during Parkinson's disease and cell loss is most extensive in the subpopulation of melanized neurones located in the substantia nigra pars compacta. Iron accumulation, together with a lack of up-regulation of the iron-storing protein, ferritin, has been reported and may contribute to increased oxidative stress in this region. We investigated the binding activity of iron regulatory protein-1 (IRP1) to the iron-responsive element that precludes ferritin mRNA translation, in the substantia nigra of a group of parkinsonian patients who presented a statistically significant reduction in the number of nigral melanized-neurones and an increased iron content, together with unchanged H-ferritin and L-ferritin subunit levels as compared to matched controls. The levels of ferritin mRNAs and the binding activity of IRP1 to the iron-responsive element of ferritin mRNA did not differ significantly between the two groups. Moreover, there was no detectable contribution of the iron regulatory protein-2 (IRP2) binding activity. No change in IRP1 control of ferritin mRNA translation explains the lack of up-regulation of ferritin expression in cytoplasmic extracts of SNpc that would be normally expected with cytosolic iron accumulation. The data of this study do not favor changes in transcription and post-transcriptional regulation of ferritin expression in Parkinson's disease and suggest a 'compartmentalized' iron accumulation.

Aged↗
PubMed2002

Mixed dementia: epidemiology, diagnosis, and treatment.

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.

Aged↗
PubMed2002

Two populations of neuronal intranuclear inclusions in SCA7 differ in size and promyelocytic leukaemia protein content.

Spinocerebellar ataxia type 7 (SCA7) is a hereditary progressive cerebellar ataxia with retinal degeneration associated with an abnormally expanded polyglutamine stretch. Neuronal intranuclear inclusions (NIIs), as in other polyglutamine diseases, are pathological hallmarks of these disorders. NIIs in polyglutamine diseases contain not only the protein with the expanded polyglutamine stretch but also other types of proteins. Several chaperone proteins related to the ubiquitin proteasome pathway, transcription factors and nuclear matrix proteins have been detected in NIIs. The composition of NIIs might reflect the process of NII formation and part of the pathogenesis of these diseases. To investigate how these proteins relate to the pathogenesis of SCA7, we performed immunohistochemical analyses of the composition of NIIs in two cases of SCA7. We demonstrated that there are two types of NIIs in SCA7 that differ in size and immunoreactivity to promyelocytic leukaemia protein (PML), one of the essential components of nuclear bodies (NBs; also called PML oncogenic domains). Small and large NIIs contained ataxin-7, human DnaJ homologue 2 (HDJ-2) and proteasome subunit 19S. In contrast, PML was found only in small NIIs. CREB-binding protein (CBP), another component of NBs, was distributed like PML in NIIs. Our results suggest that NIIs are formed by the accumulation of ataxin-7 in NBs, which become enlarged as they recruit related proteins.

Adult↗
PubMed2002

Analysis of the geographical distribution of sporadic Creutzfeldt-Jakob disease in France between 1992 and 1998.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a rare fatal dementia caused by a transmissible agent. However, the mechanism leading to the disease is unknown in the majority of cases. The presence of geographically clustered cases might indicate a common environmental exposure to the transmissible agent, or case-to-case transmission of the agent. This study sought evidence of clustering of cases of sporadic CJD in France. METHODS: A total of 402 individuals who died from definite or probable sporadic CJD in France between 1992 and 1998 were analysed. The geographical distribution of cases was analysed using three different clustering methods. An analysis of the distribution of the distances between pairs was performed to look for evidence of clustering. Then, two methods of cluster detection were used to identify the locations of clusters. RESULTS: Each of our analyses found some evidence of clustering, though the extent of that clustering differed between approaches. The strongest evidence, statistically, related to three cases living in a small rural area in South-West France (P = 0.001). Two of the three cases lived in the same area throughout life. They had also both undergone surgery on several occasions. Little information is available on the third case. CONCLUSION: Some sporadic CJD cases in France may be aetiologically linked. There was strong evidence that three cases in South-West France formed a cluster but the precise mechanism underlying this cluster of cases remains unclear. The potentially long incubation period of the disease makes the identification of links between such cases difficult.

Adult↗
PubMedDate not supplied

The vascular lesions in vascular and mixed dementia: the weight of functional neuroanatomy.

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.

Aged↗