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P Parchi

Publications and source records attributed to P Parchi.

At least 19 recordsLinked to original sources
PubMed2006

How a neuropsychiatric brain bank should be run: a consensus paper of Brainnet Europe II.

The development of new molecular and neurobiological methods, computer-assisted quantification techniques and neurobiological investigation methods which can be applied to the human brain, all have evoked an increased demand for post-mortem tissue in research. Psychiatric disorders are considered to be of neurobiological origin. Thus far, however, the etiology and pathophysiology of schizophrenia, depression and dementias are not well understood at the cellular and molecular level. The following will outline the consensus of the working group for neuropsychiatric brain banking organized in the Brainnet Europe II, on ethical guidelines for brain banking, clinical diagnostic criteria, the minimal clinical data set of retrospectively analyzed cases as well as neuropathological standard investigations to perform stageing for neurodegenerative disorders in brain tissue. We will list regions of interest for assessments in psychiatric disorder, propose a dissection scheme and describe preservation and storage conditions of tissue. These guidelines may be of value for future implementations of additional neuropsychiatric brain banks world-wide.

Brain↗
PubMed2005

Creutzfeldt-Jakob disease associated with the R208H mutation in the prion protein gene.

The authors investigated a patient who died of apparent sporadic Creutzfeldt-Jakob disease (CJD) but carried a R208H substitution in the prion protein (PrP). The patient phenotype was indistinguishable from typical sporadic CJD (i.e., MM1 subtype). In addition, pathologic PrP, PrP(Sc), originated from both the normal and the mutated PRNP allele and had the same characteristics as PrP(Sc) type 1. The authors propose that the R208H mutation influences disease susceptibility without significantly affecting PrP(Sc) properties or disease phenotype.

14-3-3 Proteins↗
PubMed2004

Sensitivity of 14-3-3 protein test varies in subtypes of sporadic Creutzfeldt-Jakob disease.

BACKGROUND: The increase of the 14-3-3 protein in CSF is used as a diagnostic test in Creutzfeldt-Jakob disease (CJD), but the sensitivity and specificity of the 14-3-3 test are disputed. One reason for the dispute may be the recently established heterogeneity of sporadic CJD. The relationship between CSF 14-3-3 protein and sporadic CJD subtypes, distinguished by electrophoretic mobility of proteinase K-resistant prion protein (PrP(Sc)) and genotype at codon 129 of the prion protein gene, has not been elucidated. METHODS: The authors examined the 14-3-3 protein test in 90 patients with sporadic CJD. PrP(Sc) type (type 1 or type 2) and the genotype at polymorphic codon 129 were determined in each patient. Mutations were excluded by prion gene sequencing. RESULTS: The authors' findings indicate that the sensitivity of the 14-3-3 test is higher in patients with molecular features of the classic sporadic CJD than in patients with the nonclassic CJD subtypes. The difference appears to be related to the PrP(Sc) type and not to the codon 129 genotype. Disease duration before 14-3-3 testing might also have an influence because it was shorter in classic sporadic CJD. CONCLUSION: The Creutzfeldt-Jakob disease clinical subtype should be considered when interpreting results of the 14-3-3 test.

14-3-3 Proteins↗
PubMed2002

Creutzfeldt-Jakob disease associated with a deletion of two repeats in the prion protein gene.

A two-octapeptide repeat deletion of the prion protein gene has been recently observed in a patient with a 2-year history of dementia and a clinical diagnosis of possible Creutzfeldt-Jakob disease (CJD). The authors report a similar deletion in a patient with a definitive diagnosis of CJD. Since the two-repeat deletion has not been observed in large, population-based studies, the two cases suggest that this deletion is a new pathogenic mutation associated with CJD.

Autopsy↗
PubMed2002

A French cluster of Creutzfeldt-Jakob disease: a molecular analysis.

We report the molecular and phenotypic analysis of a French cluster of three cases of Creutzfeldt-Jakob disease (CJD), two of them occurring in 1998 in the same village and the other in 1995 in a neighboring village. Analyses of the occurrence of these events in a close area with less than 3000 inhabitants over the 1992-1999 notification period confirmed that they are rare. This could be explained either by a common source of contamination or by the coincidental occurrence of either sporadic or genetic CJD. We applied genetic analysis and brain PrPres typing to explore these CJD cases. The three patients did not carry any mutation in their prion protein gene coding sequence. All were homozygous for methionine at the polymorphic codon 129. Brain tissue was available from two cases that died in 1998. The two patients showed different PrPres profiles on Western blot and distinct clinico-pathological features. These findings do not support the conclusion that in these three cases, CJD was acquired from a unique source of contamination and suggest that concurrent occurrence of sporadic CJD accounted for this CJD cluster.

Aged↗
PubMed2001

Creutzfeldt-Jakob disease after receipt of a previously unimplicated brand of dura mater graft.

BACKGROUND: Iatrogenic Creutzfeldt-Jakob disease (CJD) transmission via dura mater grafts has been reported in many countries. In September 1998, a 39-year-old Colorado woman was reported as having suspected CJD after receiving a dura mater graft 6 years earlier. METHODS: An investigation was initiated to confirm the diagnosis of CJD and assess the possible source of CJD transmission. The authors determined the presence or absence of other known CJD risk factors, checked for epidemiologic evidence of possible CJD transmission via neurosurgical instruments, and evaluated the procedures used in the collection and processing of the graft, including whether the donor may have had CJD. RESULTS: The CJD diagnosis was confirmed in the dural graft recipient by neuropathologic and immunodiagnostic evaluation of the autopsy brain tissue. She had no history of receipt of cadaveric pituitary hormones or corneal grafts or of CJD in her family. The authors found no patients who underwent a neurosurgical procedure within 6 months before or 5 months after the patient's surgery in 1992 who had been diagnosed with CJD. The dura mater was obtained from a 57-year-old man with a history of dysarthria, ataxia, and behavioral changes of uncertain origin. The graft was commercially prepared by use of a process that included treatment with 0.1 N sodium hydroxide and avoided commingling of dura from different donors. CONCLUSIONS: The patient's age, absence of evidence for other sources of CJD, the latent period, and the report of an unexplained neurologic illness in the donor of the dura mater indicate that the graft was the most likely source of CJD in this patient.

Adult↗
PubMed2001

Creutzfeldt-Jakob disease in unusually young patients who consumed venison.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) in humans and chronic wasting disease (CWD) in deer and elk occur in the United States. Recent reports of 3 unusually young patients with CJD who regularly consumed deer or elk meat created concern about the possible zoonotic transmission of CWD. OBJECTIVE: To examine the possible transmission of CWD to humans. PATIENTS: Three unusually young patients (aged 28, 28, and 30 years) with CJD in the United States during 1997-2000. METHODS: We reviewed medical records and interviewed family members and state wildlife and agriculture officials. Brain tissue samples were tested using histopathologic, immunohistochemical, immunoblot, or prion protein gene analyses. MAIN OUTCOME MEASURES: Presence or absence of established CJD risk factors, deer and elk hunting in CWD-endemic areas, and comparison of the evidence for the 3 patients with that of a zoonotic link between new variant CJD and bovine spongiform encephalopathy. RESULTS: None of the patients had established CJD risk factors or a history of travel to Europe. Two patients hunted game animals and 1 was a daughter of a hunter. Unlike patients with new variant CJD, the 3 patients did not have a unique neuropathologic manifestation, clinicopathologic homogeneity, uniformity in the codon 129 of the prion protein gene, or prion characteristics different from those of classic variants. CONCLUSIONS: Although the occurrence of 3 unusually young patients with CJD who consumed venison suggested a possible relationship with CWD, our follow-up investigation found no strong evidence for a causal link. Ongoing CJD surveillance remains important for continuing to assess the risk, if any, of CWD transmission to humans.

Adult↗
PubMed2000

Genetic influence on the structural variations of the abnormal prion protein.

Prion diseases are characterized by the presence of the abnormal prion protein PrP(Sc), which is believed to be generated by the conversion of the alpha-helical structure that predominates in the normal PrP isoform into a beta-sheet structure resistant to proteinase K (PK). In human prion diseases, two major types of PrP(Sc), type 1 and 2, can be distinguished based on the difference in electrophoretic migration of the PK-resistant core fragment. In this study, protein sequencing was used to identify the PK cleavage sites of PrP(Sc) in 36 cases of prion diseases. We demonstrated two primary cleavage sites at residue 82 and residue 97 for type 1 and type 2 PrP(Sc), respectively, and numerous secondary cleavages distributed along the region spanning residues 74-102. Accordingly, we identify three regions in PrP(Sc): one N-terminal (residues 23-73) that is invariably PK-sensitive, one C-terminal (residues 103-231) that is invariably PK-resistant, and a third variable region (residues 74-102) where the site of the PK cleavage, likely reflecting the extent of the beta-sheet structure, varies mostly as a function of the PrP genotype at codon 129.

Brain Chemistry↗
PubMed2000

Intracerebral distribution of the abnormal isoform of the prion protein in sporadic Creutzfeldt-Jakob disease and fatal insomnia.

Molecular genetics and protein chemistry have led to major advances in our understanding of the molecular basis of phenotypic variability of prion diseases. A large body of evidence indicates that a common methionine/valine polymorphism at codon 129 in the prion protein gene (PRNP), alone or in conjunction with PRNP mutations, modulates both disease susceptibility and phenotypic expression of human prion diseases. In addition, there are physicochemical properties of the abnormal isoform of the prion protein (PrP(sc)), such as relative molecular mass and glycosylation, that correlate with distinct phenotypes even in subjects carrying the same PRNP genotype. Different PrP(sc) "type"-PRNP genotype combinations are found associated with pathological phenotypes that differ in the relative severity of lesions among distinct brain regions, the presence and morphology of certain lesions such as amyloid plaques, and the pattern of intracerebral and tissue deposition of PrP(sc). This review summarizes the currently available data on the molecular pathology of sporadic Creutzfeldt-Jakob disease, the most common human prion disease, and fatal insomnia, a more recently defined entity that has rapidly become one of the best characterized of the human prion diseases.

Blotting, Western↗
PubMed2000

Effect of the E200K mutation on prion protein metabolism. Comparative study of a cell model and human brain.

The hallmark of prion diseases is the cerebral accumulation of a conformationally altered isoform (PrP(Sc)) of a normal cellular protein, the prion protein (PrP(C)). In the inherited form, mutations in the prion protein gene are thought to cause the disease by altering the metabolism of the mutant PrP (PrP(M)) engendering its conversion into PrP(Sc). We used a cell model to study biosynthesis and processing of PrP(M) carrying the glutamic acid to lysine substitution at residue 200 (E200K), which is linked to the most common inherited human prion disease. PrP(M) contained an aberrant glycan at residue 197 and generated an increased quantity of truncated fragments. In addition, PrP(M) showed impaired transport of the unglycosylated isoform to the cell surface. Similar changes were found in the PrP isolated from brains of patients affected by the E200K variant of Creutzfeldt-Jakob disease. Although the cellular PrP(M) displayed some characteristics of PrP(Sc), the PrP(Sc) found in the E200K brains was quantitatively and qualitatively different. We propose that the E200K mutation cause the same metabolic changes of PrP(M) in the cell model and in the brain. However, in the brain, PrP(M) undergoes additional modifications, by an age-dependent mechanism that leads to the formation of PrP(Sc) and the development of the disease.

Amino Acid Substitution↗
PubMed2000

PrP(Sc) typing by N-terminal sequencing and mass spectrometry.

The heterogeneity of the clinicopathological phenotype in human prion diseases is associated with the presence of the different forms of the abnormal prion protein, PrP(Sc). We have previously shown that PrP(Sc) in FFI and a subtype of familial CJD linked to the D178N mutation can be distinguished by their difference in gel mobility following proteinase K (PK) treatment. To further characterize the structural difference of PrP(Sc) in familial prion diseases, N-terminal sequencing and mass spectrometry were used to identify the protease cleavage sites in PrP(Sc) extracted from affected brains. We found that the main PK cleavage sites of PrP(Sc) are located at residue 97 in FFI, and residue 82 in both CJD178 and a GSS subtype linked to the P102L mutation. The differential accessibility to protease in the native PrP(Sc) suggests that PrP(Sc) exist as distinct conformers in different disease states.

Brain↗
PubMed1999

A subtype of sporadic prion disease mimicking fatal familial insomnia.

OBJECTIVE: To establish a variant of sporadic prion disease as the sporadic form of fatal familial insomnia (FFI). BACKGROUND: FFI is a recently described prion disease characterized clinically by severe sleep impairment, dysautonomia, and motor signs, and pathologically by atrophy of thalamic nuclei, especially the medial dorsal and anterior ventral, and of the inferior olive. FFI is linked to the D178N mutation coupled with the methionine codon at position 129 in the prion protein gene (PRNP). It is also identified by the properties of the abnormal prion protein (PrP(Sc)), which has the relative molecular mass of 19 kDa, corresponding to the so-called type 2, and a marked underrepresentation of the unglycosylated form relative to the diglycosylated and monoglycosylated forms. METHODS: Clinical, pathologic, PrP(Sc), and PRNP data from 5 subjects with a sporadic prion disease phenotypically similar to FFI were collected and analyzed. RESULTS: All 5 subjects had a disease clinically similar and histopathologically virtually identical to FFI. PrP(Sc) type 2 was present in all subjects in amount and distribution similar to those of FFI. However, the PrP(Sc) did not show the striking underrepresentation of the unglycosylated isoform of the protein that is characteristic of FFI. Moreover, none of the subjects had the D178N PRNP mutation but all were homozygous for methionine at codon 129. CONCLUSION: This condition is likely to represent the sporadic form of FFI and the term "sporadic fatal insomnia" is proposed.

Adult↗
PubMed1999

Abnormal diffusion-weighted magnetic resonance images in Creutzfeldt-Jakob disease.

BACKGROUND: Traditional imaging methods, including computed tomography, routine magnetic resonance imaging (MRI), and magnetic resonance spectroscopy, have not been particularly useful in the diagnosis of Creutzfeldt-Jakob disease (CJD). Although abnormalities can be seen using these methods, the findings are evident only late in the disease or lack specificity or sensitivity. OBJECTIVE: To describe abnormalities on diffusion-weighted MRIs in 4 patients with proven CJD. METHODS: Diffusion-weighted MRIs were obtained on 4 patients with CJD as part of a routine MRI brain examination. RESULTS: In all 4 patients, diffusion-weighted MRIs of the brain demonstrated bilateral hyperintensity in the basal ganglia. In 1 patient, the most conspicuous abnormality seen in diffusion-weighted images was in the thalamus. Two patients also demonstrated hyperintensity in the cerebral cortex on diffusion-weighted images. Only 2 of 4 patients demonstrated clear abnormalities on routine (non-diffusion-weighted) MRIs. Diffusion abnormalities were visible in 1 patient within 1 month of symptom onset. The findings were most conspicuous and extensive in the patient with the longest duration of symptoms (7 months). CONCLUSIONS: Diffusion-weighted MRI might provide a noninvasive method of identifying patients with CJD. However, further investigations must be performed to determine the specificity of these findings for CJD.

Basal Ganglia↗
PubMed1999

Tau gene mutation in familial progressive subcortical gliosis.

Familial forms of frontotemporal dementias are associated with mutations in the tau gene. A kindred affected by progressive subcortical gliosis (PSG), a rare form of presenile dementia, has genetic linkage to chromosome 17q21-22. This kindred (PSG-1) is included in the 'frontotemporal dementias and Parkinsonism linked to chromosome 17' group along with kindreds affected by apparently different forms of atypical dementias. Some of these kindreds have mutations in the tau gene. We report here that PSG-1 has a tau mutation at position +16 of the intron after exon 10. The mutation destabilizes a predicted stem-loop structure and leads to an over-representation of the soluble four-repeat tau isoforms, which assemble into wide, twisted, ribbon-like filaments and ultimately result in abundant neuronal and glial tau pathology. The mutations associated with PSG and other atypical dementias can be subdivided into three groups according to their tau gene locations and effects on tau. The existence of tau mutations with distinct pathogenetic mechanisms may explain the phenotypic heterogeneity of atypical dementias that previously led to their classification into separate disease entities.

Cerebral Cortex↗
PubMed1999

Protease resistant prion proteins are not present in sporadic "poor outcome" schizophrenia.

Various clinical and epidemiological data have suggested the possibility of infectious mechanisms in schizophrenia. In addition, lengthy prodromal psychiatric symptoms can presage the development of Creutzfeldt-Jakob disease, a prototypical prion disorder. Accordingly, the presence of human protease resistant prion proteins (PrPres) was assessed in postmortem frontal cortical and thalamic tissues from a prospectively accrued and well characterised sample of elderly patients with chronic, sporadic, "poor outcome" schizophrenia using a sensitive immunoblot assay. No PrPres was found in the brains of any of the cases, providing evidence against a role for abnormal prion proteins in the pathogenesis of schizophrenia.

Aged↗
PubMed1999

Type 1 protease resistant prion protein and valine homozygosity at codon 129 of PRNP identify a subtype of sporadic Creutzfeldt-Jakob disease.

A man was studied with sporadic Creutzfeldt-Jakob disease (sCJD) who had serial cortical syndromes evolving over 15 months without significant ataxia, prominent myoclonus, or periodic complexes on EEG examinations. This clinical phenotype correlated with a predominantly cortical and striatal distribution of lesions and accumulation of protease resistant prion protein with relative sparing of the brainstem or cerebellum. No amyloid plaques were seen and prion protein (PrP) immunohistochemistry only demonstrated very faint granular deposits in the cerebral cortex. Molecular analysis showed homozygosity for valine at codon 129 in the prion protein gene (PRNP) and protease resistant prion protein type 1 deposition. The comparison of molecular and clinicopathological features of the present case with those previously reported in sCJD, indicates that valine homozygosity at codon 129 and type 1 protease resistant prion protein are associated with a distinct phenotypic variant of sCJD. The data also support the view that the PRNP codon 129 polymorphism and the physicochemical properties of the protease resistant prion protein are major determinants of phenotypic variability in sCJD.

Codon↗
PubMed1999

A novel phenotype in familial Creutzfeldt-Jakob disease: prion protein gene E200K mutation coupled with valine at codon 129 and type 2 protease-resistant prion protein.

A novel phenotype of familial Creutzfeldt-Jakob disease (CJD) with mutated codon 200 of the prion protein gene (PRNP) coupled with the valine codon 129 (E200K-129V haplotype) has two features never observed in subjects carrying the pathogenic mutation coupled with the methionine codon 129 (E200K-129M haplotype): (1) plaque-like prion protein (PrP) deposits in the cerebellum and (2) type 2 protease-resistant prion protein (PrP(res)). This observation further underlines the role of codon 129 on the mutated PRNP allele in modulating the phenotype of familial prion diseases.

Aged↗