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Biomedical subjects

Charles Duyckaerts

Publications and source records attributed to Charles Duyckaerts.

At least 19 recordsLinked to original sources
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

Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques.

We describe the biological consequences on PSEN1 exons 8 or 9 splicing and Abeta peptides production of four PSEN1 mutations associated with a phenotypic variant of Alzheimer disease, which includes cotton wool plaques and spastic paraparesis (CWP/SP). Two of these mutations (c.869-22_869-23ins18 and c.871A > C, p.T291P) are novel mutations located in intron 8 and exon 9, respectively. The c.869-22_869-23ins18 mutation caused exon 9 skipping whereas the c.871A > C (p.T291P) mutation showed only a modest effect on exon 9 skipping. The previously reported E280G and P264L mutations, located in exon 8, had no effect on mRNA splicing. Infection of cells with mutant T291P, E280G, or P264L cDNAs caused a variable increase in secreted Abeta42. We conclude that none of the previously proposed mechanisms, i.e. exceptionally large increases in secreted Abeta42 levels or loss of PSEN1 exons 8 or 9, provides complete explanation of the CWP/SP phenotype.

Alzheimer Disease↗
PubMed2005

The pro-apoptotic human BH3-only peptide harakiri is expressed in cryptococcus-infected perivascular macrophages in HIV-1 encephalitis patients.

In the central nervous system (CNS), HIV-1 targets mainly microglia/macrophages. Like the CD4+ T cell depletion and neuronal loss in AIDS, apoptosis is thought to be involved in eliminating infected macrophages. In this study, we examined the expression of the pro-apoptotic BH3-peptide harakiri (Hrk) in brain tissues of AIDS patients. Immunoreactivity against Hrk was positive in perivascular macrophages infiltrated into some restricted lesions. Most of these immunopositive cells contained small inclusions positive for Grocott's methenamine silver staining. Confocal laser microscopy demonstrated that Hrk expression coincided with immunoreactivities against HIV-1 and Cryptococcus neoformans. Expression of Hrk mRNA was demonstrated in these cells by in situ hybridization, which indicated that Hrk is not phagocytosed material. Some pro-apoptotic bcl-family members, including Hrk, may contribute to the delayed hypersensitive reaction in AIDS, in macrophages eliminating opportunistic infection.

Adult↗
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

The mitochondrial complex I inhibitor rotenone triggers a cerebral tauopathy.

Reduced activity of the mitochondrial respiratory chain--particularly complex I--may be implicated in the etiology of both Parkinson's disease and progressive supranuclear palsy, although these neurodegenerative diseases differ substantially as to their distinctive pattern of neuronal cell loss and the predominance of cerebral alpha-synuclein or tau protein pathology. To determine experimentally whether chronic generalized complex I inhibition has an effect on the distribution of alpha-synuclein or tau, we infused rats systemically with the plant-derived isoflavonoid rotenone. Rotenone-treated rats with a pronounced metabolic impairment had reduced locomotor activity, dystonic limb posture and postural instability. They lost neurons in the substantia nigra and in the striatum. Spherical deposits of alpha-synuclein were observed in a few cells, but cells with abnormal cytoplasmic accumulations of tau immunoreactivity were significantly more numerous in the striatum of severely lesioned rats. Abnormally high levels of tau immunoreactivity were found in the cytoplasm of neurons, oligodendrocytes and astrocytes. Ultrastructurally, tau-immunoreactive material consisted of straight 15-nm filaments decorated by antibodies against phosphorylated tau. Many tau+ cell bodies also stained positive for thioflavin S, nitrotyrosine and ubiquitin. Some cells with abnormal tau immunoreactivity contained activated caspase 3. Our data suggest that chronic respiratory chain dysfunction might trigger a form of neurodegeneration in which accumulation of hyperphosphorylated tau protein predominates over deposits of alpha-synuclein.

Amyloid beta-Peptides↗
PubMed2005

Expression of human FE65 in amyloid precursor protein transgenic mice is associated with a reduction in beta-amyloid load.

FE65 is an adaptor protein that interacts with the cytoplasmic tail of the amyloid precursor protein (APP). In cultured non-neuronal cells, the formation of the FE65-APP complex is a key element for the modulation of APP processing, signalling and beta-amyloid (Abeta) production. The functions of FE65 in vivo, including its role in the metabolism of neuronal APP, remain to be investigated. In this study, transgenic mice expressing human FE65 were generated and crossbred with APP transgenic mice, known to develop Abeta deposits at 6 months of age. Compared with APP mice, APP/FE65 double transgenic mice exhibited a lower Abeta accumulation in the cerebral cortex as demonstrated by immunohistochemistry and immunoassay, and a lower level of APP-CTFs. The reduced accumulation of Abeta in APP/FE65 double transgenics, compared with APP mice, could be linked to the low Abeta42 level observed at 4 months of age and to the lower APP-CTFs levels. The present work provides evidence that FE65 plays a role in the regulation of APP processing in an in vivo model.

Amyloid beta-Peptides↗
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

A non-DM1, non-DM2 multisystem myotonic disorder with frontotemporal dementia: phenotype and suggestive mapping of the DM3 locus to chromosome 15q21-24.

The majority of proximal myotonic myopathy syndromes reported so far have been related to the myotonic dystrophy (DM) type 2 (DM2) mutation, an expanded (CCTG)n repeat in the ZNF9 gene. Here, we describe the phenotype and the histological features in muscle and brain of the first large pedigree with a non-myotonic dystrophy type 1 (DM1) non-DM2 multisystem myotonic disorder associated with severe frontotemporal dementia. Thirty individuals from three generations underwent detailed neurological, neuropsychological, electrophysiological, brain imaging and molecular analyses. Ten of them had proximal muscle weakness at onset, clinical/electrical myotonia and DM-type cataracts. The mean age at onset was 46.7 +/- 12.6 years (range: 32-69). Dementia was observed later in the course of the disease. On muscle biopsies, rare nuclear clumps, rimmed vacuoles and small angulated type 1 and type 2 fibres were seen early in the disease. They were replaced by fibrous adipose tissue at later stages. Immunohistochemical analysis of myosin heavy chain isoforms showed no selective fibre type atrophy-both type 1 and type 2 fibres being affected. Cortical atrophy without white matter lesions was seen on brain MRI. A brain single photon emission computed tomography (SPECT) study revealed marked frontotemporal hypoperfusion. Post-mortem examination of the brains of two patients showing prominent frontotemporal spongiosis, neuronal loss and rare neuronal and glial tau inclusions suggested frontotemporal dementia. Western blot analyses of the tau protein showed a triplet of isoforms (60, 64 and 69 kDa) in neocortical areas, and a doublet (64 and 69 kDa) in subcortical areas that distinguish our myotonic disorder from other's myotonic dystrophies. Molecular analyses failed to detect a repeat expansion in the DMPK and ZNF9 genes excluding both DM1 and DM2, whereas a genome-wide linkage analysis strongly suggested a linkage to chromosome 15q21-24. This previously unreported multisystem myotonic disorder including findings resembling DM1, DM2 and frontotemporal dementia provides further evidence of the clinical and genetic heterogeneity of the myotonic dystrophies. We propose to designate this disease myotonic dystrophy type 3, DM3.

Adult↗
PubMed2004

Dopamine depletion impairs precursor cell proliferation in Parkinson disease.

Cerebral dopamine depletion is the hallmark of Parkinson disease. Because dopamine modulates ontogenetic neurogenesis, depletion of dopamine might affect neural precursors in the subependymal zone and subgranular zone of the adult brain. Here we provide ultrastructural evidence showing that highly proliferative precursors in the adult subependymal zone express dopamine receptors and receive dopaminergic afferents. Experimental depletion of dopamine in rodents decreases precursor cell proliferation in both the subependymal zone and the subgranular zone. Proliferation is restored completely by a selective agonist of D2-like (D2L) receptors. Experiments with neural precursors from the adult subependymal zone grown as neurosphere cultures confirm that activation of D2L receptors directly increases the proliferation of these precursors. Consistently, the numbers of proliferating cells in the subependymal zone and neural precursor cells in the subgranular zone and olfactory bulb are reduced in postmortem brains of individuals with Parkinson disease. These observations suggest that the generation of neural precursor cells is impaired in Parkinson disease as a consequence of dopaminergic denervation.

Animals↗
PubMed2004

alpha-Internexin aggregates are abundant in neuronal intermediate filament inclusion disease (NIFID) but rare in other neurodegenerative diseases.

Abnormal neuronal aggregates of alpha-internexin and the three neurofilament (NF) subunits, NF-L, NF-M, and NF-H have recently been identified as the pathological hallmarks of neuronal intermediate filament (IF) inclusion disease (NIFID), a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal and extrapyramidal signs. alpha-Internexin, a class IV IF protein, a major component of inclusions in NIFID, has not previously been identified as a component of the pathological protein aggregates of any other neurodegenerative disease. Therefore, to determine the specificity of this protein, alpha-internexin immunohistochemistry was undertaken on cases of NIFID, non-tau frontotemporal dementias, motor neuron disease, alpha-synucleinopathies, tauopathies, and normal aged control brains. Our results indicate that class IV IF proteins are present within the pleomorphic inclusions of all cases of NIFID. Small subsets of abnormal neuronal inclusions in Alzheimer's disease, Lewy body diseases, and motor neuron disease also contain epitopes of alpha-internexin. Thus, alpha-internexin is a major component of the neuronal inclusions in NIFID and a relatively minor component of inclusions in other neurodegenerative diseases. The discovery of alpha-internexin in neuronal cytoplasmic inclusions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological filamentous neuronal inclusions.

Adult↗
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

Behavioral disorder, dementia, ataxia, and rigidity in a large family with TATA box-binding protein mutation.

BACKGROUND: Spinocerebellar ataxia type 17 is an autosomal dominant cerebellar ataxia caused by a CAG repeat expansion in the TATA box-binding protein gene. Ataxia is typically the first sign whereas behavioral symptoms occur later. OBJECTIVE: To characterize the unusual phenotypic expression of a large spinocerebellar ataxia type 17 kindred. DESIGN: Clinical, neuropathological, and molecular genetic characterization of a 4-generation family with 16 affected patients. RESULTS: Behavioral symptoms and frontal impairment dominated the early stages preceding ataxia, rigidity, and dystonic movements. Neuropathological examination showed cortical, subcortical, and cerebellar atrophy. Purkinje cell loss and gliosis, pseudohypertrophic degeneration of the inferior olive, marked neuronal loss and gliosis in the caudate nucleus, and in the medial thalamic nuclei were salient features together with neuronal intranuclear inclusions stained with anti-TATA box-binding protein and antipolyglutamine antibodies. The disease was caused by a stable 52 CAG repeat expansion of the TATA box-binding protein gene, although there was apparent variability in the age of onset. CONCLUSION: The characteristics of this family broaden the clinical picture of spinocerebellar ataxia type 17: initial presenile dementia with behavioral symptoms should be added to ataxia, rigidity, and dystonic movements, which are more commonly encountered.

Adult↗
PubMed2004

Subcellular topography of neuronal Abeta peptide in APPxPS1 transgenic mice.

In transgenic mice expressing human mutant beta-amyloid precursor protein (APP) and mutant presenilin-1 (PS1), Abeta antibodies labeled granules, about 1 microm in diameter, in the perikaryon of neurons clustered in the isocortex, hippocampus, amygdala, thalamus, and brainstem. The granules were present before the onset of Abeta deposits; their number increased up to 9 months and decreased in 15-month-old animals. They were immunostained by antibodies against Abeta 40, Abeta 42, and APP C-terminal region. In double immunofluorescence experiments, the intracellular Abeta co-localized with lysosome markers and less frequently with MG160, a Golgi marker. Abeta accumulation correlated with an increased volume of lysosomes and Golgi apparatus, while the volume of endoplasmic reticulum and early endosomes did not change. Some granules were immunolabeled with an antibody against flotillin-1, a raft marker. At electron microscopy, Abeta, APP-C terminal, cathepsin D, and flotillin-1 epitopes were found in the lumen of multivesicular bodies. This study shows that Abeta peptide and APP C-terminal region accumulate in multivesicular bodies containing lysosomal enzymes, while APP N-terminus is excluded from them. Multivesicular bodies could secondarily liberate their content in the extracellular space as suggested by the association of cathepsin D with Abeta peptide in the extracellular space.

Amyloid beta-Peptides↗
PubMed2004

alpha-internexin is present in the pathological inclusions of neuronal intermediate filament inclusion disease.

Neuronal intermediate filament (IF) inclusion disease (NIFID) is a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal, and extrapyramidal signs. Pathologically, in affected areas, there is neuronal loss, astrocytosis, and neuronal intracytoplasmic aggregates of abnormal neuronal IFs that contain neither tau nor alpha-synuclein. Thus, to characterize the neuronal IF protein profile of inclusions in NIFID, immunohistochemistry (IHC) was performed on 10 cases of NIFID, four normal aged controls (NL), and two cases of Alzheimer's disease (AD) using a panel of anti-neuronal IF proteins. Immunoelectron microscopy was performed on selected cases and frozen tissue from the frontal lobe of four cases was used for biochemical studies including sequential extractions and Western blotting. Based on these studies, we report here for the first time that alpha-internexin, a neuronal IF protein, is present within the inclusions of NIFID as are all three neurofilament subunits: heavy, medium, and light. Thus, all class IV neuronal IF proteins are present within the pathological inclusions of this disease. Biochemistry revealed that IF aggregates were soluble in sodium dodecyl sulfate (SDS) and no post-translational modification was detected when compared with Alzheimer's disease or aged control brains. Hence, we conclude that NIFID is characterized by the pathological cytoplasmic aggregation of all class IV neuronal IF proteins in brain. The discovery of alpha-internexin in the cytoplasmic inclusions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological accumulations of IFs.

Adult↗