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Y Robitaille

Publications and source records attributed to Y Robitaille.

At least 37 records · Page 2Linked to original sources
PubMed1999

Synapses in the hereditary ataxias.

The goal of this investigation was the systematic assessment of synapses in the hereditary ataxias by the immunocytochemical and immunofluorescent visualization of SNAP-25, a protein of the presynaptic membrane. Sections were prepared from the cerebellar cortex, dentate nucleus, basis pontis, inferior olivary nuclei, and the spinal cord in 57 cases of autosomal dominant and recessive ataxia. The neuropathological phenotype included 18 cases of olivopontocerebellar atrophy (OPCA), 14 cases of familial cortical cerebellar atrophy (FCCA), 4 cases of Machado-Joseph disease (MJD), and 21 cases of Friedreich's ataxia (FA). Among the autosomal dominant ataxias, spinocerebellar ataxia type 1 (SCA-1), SCA-2, MJD/SCA-3, and SCA-6 were represented. Expanded guanine-adenine-adenine trinucleotide repeats were confirmed in 7 patients with FA. The abundance of SNAP-25 was estimated by comparing the fluorescence of the regions of interest to that of the frontal cortex, which was considered unaffected by the disease process. Despite severe Purkinje cell loss, abundant SNAP-25 reaction product remained in the molecular layer of FCCA and OPCA. Among the cases of OPCA, those identified as SCA-2 showed the most severe overall synaptic destruction in cerebellum and brain stem. In SCA-1, which caused either OPCA or FCCA, significant synaptic loss was restricted to the inferior olivary nuclei. Sparing of cerebellar cortex and inferior olivary nuclei was the rule for MJD/SCA-3 and FA, though the dentate nucleus showed reduced SNAP-25 immunoreactivity in both ataxias. In FA, preservation of SNAP-25 in the dentate nucleus was characteristic of long survival. Severe cases with short survival revealed synaptic depletion of the dentate nucleus. At the level of the spinal cord, synaptic loss in the dorsal nuclei of Clarke characterized FA and MJD/SCA-3. The inexorable clinical progression of the hereditary ataxias could not be attributed to synaptic loss in a single anatomic structure of cerebellum, brain stem, or spinal cord. Nevertheless, synaptic loss in dentate and inferior olivary nuclei correlated more precisely with the severity of the ataxia than the changes in the cerebellar cortex.

Adolescent↗
PubMed1998

Human immunodeficiency virus type 1 Vpr localization: nuclear transport of a viral protein modulated by a putative amphipathic helical structure and its relevance to biological activity.

Protein import into the nucleus is generally considered to involve specific nuclear localization signals (NLS) though it is becoming increasingly clear that efficient and well controlled import of proteins which lack a canonical NLS also occurs in cells. Human immunodeficiency virus type 1 (HIV-1) Vpr is one such protein which does not have an identifiable canonical NLS and yet efficiently localizes to the nuclear compartment. Here, we use confocal microscopy to demonstrate that mutations in the putative central hydrophobic helix of Vpr result in the retention of the protein in highly localized ring-like structures around the nuclear periphery with striking impairment in their ability to enter the nuclear interior. By characterizing other biological activities associated with this protein, such as its ability to incorporate into budding virions and its ability to arrest cells in G2, we show that this helical domain is specific for the nuclear translocation of the protein with very little effect on these other functions. Interestingly, however, perturbation of this helical motif also perturbs the protein's ability to augment viral replication in primary human macrophages indicating that the integrity of this secondary structure is essential for optimal infection in these non-dividing cells.

Amino Acid Sequence↗
PubMed1998

Vulnerable neuronal subsets in Alzheimer's and Pick's disease are distinguished by their tau isoform distribution and phosphorylation.

Aggregated tau proteins constitute the basic matrix of neuronal inclusions specific to numerous neurodegenerative disorders. Monodimensional and two-dimensional Western blot analyses performed on cortical brain homogenates allowed discrimination between disease-specific tau protein profiles. These observations raised the issue of the physiopathological significance of such specificities. Alzheimer's disease (AD) pathological tau proteins (PTPs) (tau 74, 69, 64, 55) were compared with those of Pick's disease (PiD) (tau 64, 55) using a panel of antibodies against peptidic sequences of tau isoforms corresponding to exons 2, 3, and 10. AD and PiD could then be critically differentiated by the absence of translated tau isoforms with exon 10 in PiD PTPs, along with the absence of the phosphorylation site on Ser262. Immunohistochemical studies corroborate these findings. Indeed, Pick bodies were strongly immunostained by an anti-"exon 2" antibody but failed to reveal any anti-exon 10 reactive epitope. Tangles in AD contained exon 2, 3, and 10 epitopes. Altogether, our results demonstrated that Pick bodies develop within specific neuronal subsets that express specific patterns of 7 isoforms lacking exon 10 peptidic sequence. We conclude that neurodegenerative disorders imply attrition of selectively vulnerable neuronal subsets, a process revealed, and may be sustained by specific tau isoform patterns.

Alzheimer Disease↗
PubMed1998

Double pathology in Rasmussen's syndrome: a window on the etiology?

The syndrome of chronic encephalitis with epilepsy (Rasmussen's syndrome) typically occurs in children and is characterized by the development of intractable focal seizures, progressive hemiparesis and intellectual deterioration. The etiology is unknown, and the pathological abnormalities vary from those of active disease, with numerous microglial nodules, with or without neuronophagia, perivascular round cells and glial scarring, to those of remote disease, demonstrated by neuronal loss, gliosis and perivascular round cells but few microglial nodules. We describe five patients presenting with clinical features typical of Rasmussen's syndrome, in whom pathological examination showed a second, previously unsuspected pathology in addition to the changes of chronic encephalitis. Two of the patients had vascular abnormalities bearing some resemblance to cavernous angiomata, one had a tumor, one had tuberous sclerosis, and one the forme fruste of tuberous sclerosis. The coexistence of a second pathology in these patients may provide information about the underlying mechanism of this rare condition.

Adolescent↗
PubMed1998

Structural correlates of cognitive deficits in a selected group of patients with Alzheimer's disease.

OBJECTIVE: The objective of this study was to correlate the densities of neurofibrillary tangles (NFTs) and senile plaques (SPs) in 10 patients with Alzheimer's disease (AD) with comprehensive neuropsychological data obtained within 1 year of death. BACKGROUND: Clinicopathologic studies in AD have been essentially limited to correlate neuropathologic data with severity of dementia. Very few studies have addressed the correlations between distribution of lesions and specific cognitive deficits. This is partly due to the limitation imposed by the interval between the last neuropsychological evaluation and death. METHODS: Ten patients with a postmortem diagnosis of AD, with a mean age at death of 80.4+/-6.6 years and a mean duration of symptoms of 5.6+/-2.9 years, were selected for the study. All of these patients were submitted to neuropsychological testing within 1 year of death, including 17 tests assessing memory, language, visuoperceptual, visuospatial, and constructional abilities as well as limb praxis. The neuropathologic study was performed using a modified Bielschowsky technique. Mean densities of SPs and NFTs were determined in the hippocampal formation (CA1, subiculum, and parasubiculum) and in six neocortical areas (midfrontal, orbitofrontal, cingulum, fusiform gyrus, superior and inferior parietal cortices). Statistical correlations were determined between cognitive scores and SP and NFT densities. RESULTS: For NFTs, significant correlations emerged only between tangle density in CA1 and visuoperceptual scores. For SP density values, significant correlations were found between visuoperceptual tests and lesions in the subiculum and in the fusiform gyrus, significant correlations were found between language scores and SPs in the superior parietal cortex and between visuospatial deficits and lesions in the superior parietal cortex and fusiform gyrus. CONCLUSIONS: SPs in specific brain areas displayed a good correlation with the cognitive deficits detected in this selected group of AD patients. The association of fusiform gyrus and superior parietal lobule involvement with visuoperceptual and visuospatial deficits, respectively, is in agreement with current knowledge of the anatomic basis of visual processing.

Aged↗
PubMed1997

The neuropathology of CAG repeat diseases: review and update of genetic and molecular features.

Classification of inherited neurodegenerative diseases is increasingly based on their genetic features, which supplement, clarify, and sometimes replace the older clinical and pathologic schemata. This change has been particularly rapid and impressive for the CAG repeat disorders. In Huntington's disease, X-linked spinobulbar muscular atrophy, dentatorubropallidoluysian atrophy, and a series of autosomal dominant cerebellar atrophies, genetic advances have resolved many nosologic issues, and opened new avenues for exploration of pathogenesis. In this review, we summarize classic and current concepts in neuropathology of these CAG repeat diseases.

Genetic Linkage↗
PubMed1997

Psychogeriatric clinical, electro-encephalographic and autopsy findings.

Demographic, psychiatric, and electro-encephalographic (EEG) data were compared with brain autopsy findings for 73 elderly psychiatric patients. A late onset of depression (60+ years) was more likely than early onset to be accompanied by Alzheimer's disease. There were strong associations between clinical and histopathological indicators of Alzheimer's disease. This was particularly evident for diffuse EEG slowing. Clinical as well as histopathological indicators of Alzheimer's disease were intensely related to EEG features, mainly EEG slowness (positive), reactivity to eye opening (negative) and dominant frequency (negative). Cerebrovascular pathology showed fewer EEG correlations. The results support the usefulness of the clinical electro-encephalogram in patients suspected to have Alzheimer's disease.

Age Factors↗
PubMed1997

Chronic encephalitis and epilepsy in adults and adolescents: a variant of Rasmussen's syndrome?

Chronic encephalitis and epilepsy (Rasmussen's encephalitis) is a rare progressive disorder of uncertain etiology that usually occurs in children, producing focal epilepsy, hemiparesis, and intellectual deterioration. We identified 13 patients in whom seizures developed in adolescence or adulthood with a pathologic picture of chronic encephalitis. The clinical characteristics were more variable than those occurring in children, with the patients falling into three groups: five patients developed seizures in adulthood, but otherwise showed many resemblances to the childhood form; five developed seizures in adolescence, with similar presentation but rather more benign course than in the younger patients; and three presented with clinical features initially suggestive of a tumor. Occipital onset to the seizures appeared to be more common than in the childhood form, and bilateral disease also occurred.

Adolescent↗
PubMed1997

Striatal dopamine nerve terminal markers but not nigral cellularity are reduced in spinocerebellar ataxia type 1.

We previously reported markedly reduced (-76%) dopamine (DA) levels in the putamen of seven patients with spinocerebellar ataxia type 1 (SCA1) who had no evidence of nigral cell loss or parkinsonism. To determine whether the DA reduction was accompanied by loss of DA nerve terminals, we measured levels of the DA transporter ([3H]WIN, 35,428 binding; DA transporter protein) and the vesicular monoamine transporter ([3H]DTBZ binding) in the putamen of these patients. As compared with the controls (n = 14), mean putamen concentrations of [3H]WIN 35,428 binding (-45%), dopamine transporter protein (-61%), and [3H]DTBZ binding (-48%) were significantly reduced in this SCA1 subgroup. We conclude that the degeneration in nigrostriatal DA neurons begins at the nerve ending in SCA1.

Adult↗
PubMed1996

Limits of clinical assessment in the accurate diagnosis of Machado-Joseph disease.

BACKGROUND: Machado-Joseph disease (MJD) is a type of autosomal dominant spinocerebellar ataxia for which molecular diagnosis is available. We identified 4 families segregating the MJD mutation in which no unequivocal clinical diagnosis could be established prior to molecular testing. Ethnic background, clinical, and molecular characteristics of 19 individuals carrying the MJD mutation in these 4 families were compared with a group of 32 Portuguese families who were clinically diagnosed as having MJD and were found to carry the MJD mutation. RESULTS: Several factors seemed to have an impact in the accuracy of the clinical diagnosis, such as ethnic origin; the number of affected individuals available for examination in each family; the absence of patients showing specific clinical features, such as extrapyramidal signs; and the size of the expanded CAG repeat in the MJD gene. CONCLUSION: Since the recognition of MJD based solely on clinical grounds might sometimes be misleading, a search for the MJD mutation should be performed in patients with a clinical diagnosis of spinocerebellar degeneration.

Adult↗
PubMed1996

Somatic mosaicism in the central nervous system in spinocerebellar ataxia type 1 and Machado-Joseph disease.

Spinocerebellar ataxia type 1 and Machado-Joseph disease are two autosomal dominant cerebellar ataxias caused by expansions of unstable CAG repeats in the coding region of the causative genes. The selectivity of cell death and the resulting characteristic neuropathological features in each of these diseases are not explained by the gene expression patterns. Since the repeat size correlates with age at onset and severity of these diseases, somatic mosaicism, the result of mitotic instability of the CAG repeat, could be the basis for specificity of neurodegeneration; brain structures with larger expanded repeats would be more severely affected. To study the association between neuropathological changes and somatic mosaicism of the CAG repeat size in the central nervous system of patients with these two ataxias, we determined the size of the (CAG)n expansion in 20 different regions of the brain, brainstem, cerebellum, and spinal cord from 3 patients with spinocerebellar ataxia type 1 and 3 with Machado-Joseph disease; these regions were selected for their differential neuropathological involvement in the two disorders. We observed a considerable homogeneity of repeat size ranges in all but 1 of the 20 regions examined: The cerebellar cortex showed slightly smaller (CAG)n tracts in all specimens from both groups of patients. Our results suggest that the pattern of repeat size mosaicism, similar in spinocerebellar ataxia type 1 and Machado-Joseph disease, reflects the developmental pathways and cell composition of different central nervous system regions and is not the cause of selective cell death in these disorders.

Age of Onset↗
PubMed1996

Immunoreactive levels of alpha-ketoglutarate dehydrogenase subunits in Friedreich's ataxia and spinocerebellar ataxia type 1.

Enzyme activities of a alpha-ketoglutarate dehydrogenase complex (alpha KGDHC) and one of its constituent subunits, dihydrolipoamide dehydrogenase (E3), are reported to be reduced in non-CNS tissues of some patients with Friedreich's ataxia (FA); however, the results are highly conflicting. To determine whether an enzyme abnormality occurs in brain, we measured immunoreactive levels of the three alpha KGDHC subunits, namely, alpha-ketoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and E3 in postmortem frontal, occipital and cerebellar cortices of 18 control subjects, 9 patients with FA and, for comparison, 12 patients with spinocerebellar ataxia type 1 (SCA1). Decreased (-20 to -31%) levels of E3 were observed in all three examined areas of the patients with FA with the changes statistically significant in cerebellar and frontal cortices. The E3 reduction could be explained by a loss of alpha KGDHC or other dehydrogenase complexes (e.g. pyruvate dehydrogenase complex) which utilize this subunit. In SCA1, enzyme changes were limited to E2 in cerebellar (-26%) and frontal (-19%) cortices. Although the E3 and E2 reductions are only slight, and may represent secondary events, the changes in this key Krebs cycle enzyme could exacerbate degenerative processes in both of the spinocerebellar ataxia disorders.

Acyltransferases↗
PubMed1996

Alzheimer's disease: preliminary study of spatial distribution at birth place.

Alzheimer's disease (AD) is a neurodegenerative disorder which is characterized by a progressive loss of memory and the alteration of cognitive functions. At least three chromosomal segments have been associated with early-onset AD in genetic linkage studies. These results argue for a certain degree of heterogeneity in the genetic origin of some forms of AD, although environmental risk factors cannot be ruled out in late-onset AD. In this preliminary study, we analyzed the geographical distribution of the birth places of a sample of 235 AD cases born in a defined region of Quebec (Canada), between 1895 and 1935. We wished to test the hypothesis that risk factors acting at, or around birth place and time play a role in the etiology of AD. The field of study was divided into rural and urban areas. A reference population of live births was used to compute a measure of odds ratio (OR). The OR results showed a statistically significant excess of AD cases in the rural area as compared to the reference population. When stratified for sex, the OR results showed a global excess of female AD cases in both the rural and the urban areas. For men, only the urban area presented a statistically significant deficit. We also analyzed the structures of the genealogical kinships of the rural and urban sub-groups. Although AD cases from the rural sub-group were more closely related to each other than those from the urban one, removal of the kin pairs from the OR analysis seemed to have little effect on the rural/urban distribution of cases. Therefore, the OR results would not appear to be due primarily to a difference in the kinship structures of the two sub-groups. This could mean that some risk factors for AD afflict women more strongly than men, the effect being different depending on the urban or rural origin. However, potential biases such as a higher rate of report for women, differential migration between birth places or a differential mortality ratio between sexes could produce spurious results in the direction of what we have observed in this preliminary study.

Aged↗
PubMed1996

Season of birth and Alzheimer's disease: a population-based study in Saguenay-Lac-St-Jean/Québec (IMAGE Project).

The birth distribution of 399 cases of Alzheimer's disease (AD) identified in the region of Saguenay-Lac-St-Jean (Québec) was compared with that of: (a) the population currently living in the area; and (b) the population born during the same period in the same area. AD cases have been recruited since 1986 by the IMAGE Project. Cases and controls were grouped according to the month of birth and according to the day of birth using density estimation. Analyses showed a significant deficit of births in the month of May. We believe these preliminary results deserve further attention and we suggest two possible explanations that could lead to a deficit of AD births at specific periods during the year.

Aged↗
PubMed1996

Specific pathological Tau protein variants characterize Pick's disease.

Pick's disease (PiD) is characterized by a pan-laminar frontotemporal cortical atrophy, widespread degeneration of the white matter, chromatolytic neurons, and Pick bodies (PB). Microtubule-associated Tau proteins are the main cytoskeletal components modified during the neurodegenerative changes. In the present study, pathological alterations of Tau proteins were investigated in the brains of five PiD cases at both neuropathological and biochemical levels, using the monoclonal antibody AD2 which recognizes a phosphorylation-dependent Tau epitope and strongly labeled PB. A large number of cortical and subcortical regions were studied on frozen materials. Tau proteins were analyzed on mono- and two-dimensional gel electrophoreses using a quantitative western blot approach. In all specimens, a 55 and 64 kDa Tau doublet was observed in limbic, frontal, and temporal cortices as well as in striatum and substantia nigra. In contract, Alzheimer's disease (AD) brains are characterized by the presence of the 55, 64, and 69 kDa Tau triplet whereas the 64 and 69 kDa doublet is more typical of the progressive supranuclear palsy and corticobasal degeneration. Thus, the 55 and 64 kDa doublet appears to be specific to PiD, less acidic than AD Tau proteins, and well correlated with the presence of PB.

Aged↗
PubMed1996

Familial and sporadic Alzheimer's disease: neuropathology cannot exclude a final common pathway.

Whether all etiologic forms of Alzheimer's disease (AD) share a final common pathway is a major issue. We determined the severity and regional distribution of neuronal loss, amyloid plaques, neuritic plaques (NPs), and neurofibrillary tangles (NFTs), and calculated the ratio of neuronal loss to NPs and NFTs in brains of 19 familial AD (FAD) patients with linkage to chromosome 14, six AD patients with mutations of chromosome 21 (codon 717 of the beta-amyloid percursor protein gene), and 11 sporadic AD (SAD) patients. There was no difference in the pattern of distribution of the various pathologic features or in the ratio of neuronal loss to NPs or NFTs in any AD group. However, FAD groups could be distinguished from SAD by the greater severity and the lack of influence of apolipoprotein E genotype on pathology. These differences may reflect differences in age at onset rather than different etiopathologic mechanisms. The similarity of pathologic findings in the different AD groups provides evidence for a final common pathophysiologic pathway in AD.

Age of Onset↗
PubMed1995

Distribution of brain cytochrome oxidase activity in various neurodegenerative diseases.

Cytochrome oxidase (CO) is the terminal complex of the mitochondrial respiratory chain which generates ATP by oxidative phosphorylation. We have measured CO activity in six different brain regions of patients with senile dementia of Alzheimer type (SDAT, n = 10), presenile dementia of Alzheimer type (PDAT, n = 10), Lewy body dementia with SDAT (LBD, n = 5), cerebrovascular dementia (CVD, n = 10), Parkinson dementia (PD, n = 5), and in controls (n = 8), as all confirmed by neuropathological evaluation. CO activity was lower in the frontal and parietal cortex of SDAT patients compared to controls. Patients with PDAT, LBD, CVD or PD showed no significant reduction of the enzymatic activity in the six regions studied. Our results show that reduced CO activity might play a role in the physiopathology of senile dementia of Alzheimer type.

Aged↗