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P Parchi

Publications and source records attributed to P Parchi.

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

Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects.

Phenotypic heterogeneity in sporadic Creutzfeldt-Jakob disease (sCJD) is well documented, but there is not yet a systematic classification of the disease variants. In a previous study, we showed that the polymorphic codon 129 of the prion protein gene (PRNP), and two types of protease-resistant prion protein (PrP(Sc)) with distinct physicochemical properties, are major determinants of these variants. To define the full spectrum of variants, we have examined a series of 300 sCJD patients. Clinical features, PRNP genotype, and PrP(Sc) properties were determined in all subjects. In 187, we also studied neuropathological features and immunohistochemical pattern of PrP(Sc) deposition. Seventy percent of subjects showed the classic CJD phenotype, PrP(Sc) type 1, and at least one methionine allele at codon 129; 25% of cases displayed the ataxic and kuru-plaque variants, associated to PrP(Sc) type 2, and valine homozygosity or heterozygosity at codon 129, respectively. Two additional variants, which included a thalamic form of CJD and a phenotype characterized by prominent dementia and cortical pathology, were linked to PrP(Sc) type 2 and methionine homozygosity. Finally, a rare phenotype characterized by progressive dementia was linked to PrP(Sc) type 1 and valine homozygosity. The present data demonstrate the existence of six phenotypic variants of sCJD. The physicochemical properties of PrP(Sc) in conjunction with the PRNP codon 129 genotype largely determine this phenotypic variability, and allow a molecular classification of the disease variants.

Adult↗
PubMed1998

Different patterns of truncated prion protein fragments correlate with distinct phenotypes in P102L Gerstmann-Sträussler-Scheinker disease.

The clinicopathological phenotype of the Gerstmann-Sträussler-Scheinker disease (GSS) variant linked to the codon 102 mutation in the prion protein (PrP) gene (GSS P102L) shows a high heterogeneity. This variability also is observed in subjects with the same prion protein gene PRNP haplotype and is independent from the duration of the disease. Immunoblot analysis of brain homogenates from GSS P102L patients showed two major protease-resistant PrP fragments (PrP-res) with molecular masses of approximately 21 and 8 kDa, respectively. The 21-kDa fragment, similar to the PrP-res type 1 described in Creutzfeldt-Jakob disease, was found in five of the seven subjects and correlated with the presence of spongiform degeneration and "synaptic" pattern of PrP deposition whereas the 8-kDa fragment, similar to those described in other variants of GSS, was found in all subjects in brain regions showing PrP-positive multicentric amyloid deposits. These data further indicate that the neuropathology of prion diseases largely depends on the type of PrP-res fragment that forms in vivo. Because the formation of PrP-res fragments of 7-8 kDa with ragged N and C termini is not a feature of Creutzfeldt-Jakob disease or fatal familial insomnia but appears to be shared by most GSS subtypes, it may represent a molecular marker for this disorder.

Adult↗
PubMed1998

Prion encephalopathy with insertion of octapeptide repeats: the number of repeats determines the type of cerebellar deposits.

We studied modifications of the molecular layer of the cerebellum in three patients with octapeptide repeat insertion (OPRI). Two brothers carrying a six-OPRI showed only spongiosis in haematoxylin & eosin preparations (H&E), whereas immunocytochemical examination (ICC) with an antiprion protein (PrP) antibody revealed numerous elongated PrP deposits. The third patient from a family with an eight-OPRI had numerous plaques visible in H&E preparations and had been diagnosed as Gerstmann-Straüssler-Scheinker syndrome. So far, 15 other cases from seven families and three individual cases with OPRI have undergone neuropathological examination. Characteristic PrP deposits were seen in six other cases, two isolated cases with a four- and a seven-OPRI, whereas four cases with a six-OPRI came from three different families. Such deposits have never been reported in other cases of prion encephalopathy, without OPRI. Genuine plaques were observed in five out of the 15 other patients. Interestingly, four had an eight-OPRI and one a nine-OPRI. Cases with OPRI are prone to develop different PrP deposits: those only visible on ICC are not to be confused with genuine plaques visible in H&E preparations. Elongated PrP deposits are present in cases with a four- to seven-OPRI, whereas plaques are present when there is an eight- or a nine-OPRI. All these cases should be termed prion encephalopathy with OPRI.

Adult↗
PubMed1998

Neuronal apoptosis in fatal familial insomnia.

The possibility that neuronal loss in prion diseases occurs through an apoptotic process has been postulated and is consistent with the lack of inflammation in these disorders. In order to test this hypothesis in FFI, in which neuronal loss is the predominant neuropathological feature, we examined samples of thalamus, basal ganglia, cerebral cortex, cerebellum and medulla from 10 subjects with FFI. All the patients had the characteristic 178 N mutation of the PrP gene. Eight subjects were homozygous methionine/methionine at codon 129 and 2 were heterozygous methionine/valine. Apoptotic neurons were identified by in situ end labelling in all the FFI cases and in none of the controls. They were mostly found in damaged regions and their presence and abundance seemed to correlate closely with the neuronal loss. They were particularly abundant in the thalamus and medullary olives. In heterozygous cases who had a longer disease duration and more widespread cerebral changes, apoptotic neurons were also found in the neocortex and striatum. The abundance of apoptotic neurons also correlated well with microglial activation as demonstrated by the expression of major histocompatibility complex class II antigens. PrPres immunostaining was almost invariably negative, consistent with previous data showing the lack of obvious correlation between neuronal loss and PrPres deposits in prion diseases.

Adult↗
PubMed1998

Molecular pathology of fatal familial insomnia.

Fatal familial insomnia (FFI) is linked to a mutation at codon 178 of the prion protein gene, coupled with the methionine codon at position 129, the site of a methionine/valine polymorphism. The D178N mutation coupled with the 129 valine codon is linked to a subtype of Creutzfeldt-Jakob disease (CJD178) with a different phenotype. Two protease resistant fragments of the pathogenic PrP (PrPres), which differ in molecular mass, are associated with FFI and CJD178, respectively, suggesting that the two PrPres have different conformations and hence they produce different disease phenotypes. FFI transmission experiments, which show that the endogenous PrPres recovered in affected syngenic mice specifically replicates the molecular mass of the FFI PrPres inoculated and is associated with a phenotype distinct from that of the CJD178 inoculated mice, support this idea. The second distinctive feature of the FFI PrPres is the underrepresentation of the unglycosylated PrPres form. Cell models indicate that the underrepresentation of this PrPres form results from the PrP dysmetabolism caused by the D178N mutation and not from the preferential conversion of the glycosylated forms. Codon 129 on the normal allele further modifies the FFI phenotype determining patient subpopulations of 129 homozygotes and heterozygotes: disease duration is generally shorter, insomnia more severe and histopathology more restricted to the thalamus in the homozygotes than in the heterozygotes. The allelic origin of PrPres fails to explain this finding since in both cases FFI PrPres is expressed only by the mutant allele. Despite remarkable advances, many issues remain unsolved precluding full understanding of the FFI pathogenesis.

Brain↗
PubMed1998

Creutzfeldt-Jakob disease with long duration and panencephalopathic lesions: molecular analysis of one case.

A 49-year-old woman presented with isolated aphasia followed by dementia and ataxia with a duration of 4 years. Histopathologically there was panencephalic involvement, status spongiosus, and kuru-type plaques. Molecular analysis showed heterozygosity at codon 129 in the prion protein (PrP) gene, and type 2 protease-resistant PrP. The comparison between this case and those previously reported suggests that the panencephalopathic variant of Creutzfeldt-Jakob disease (CJD) is an aspecific end-stage condition displayed by most if not all CJD variants in individual patients with an unusually prolonged course.

Biopsy↗
PubMed1998

Fatal familial insomnia in a new Italian kindred.

The authors report a new kindred with fatal familial insomnia (FFI)--an inherited prion disease. The propositus had behavioral, sleep, cognitive, and motor impairment associated with thalamic and olivary atrophy. Spongiosis was confined to the parahippocampal gyrus. Protease-resistant prion protein (PrP(res)) was present with widespread distribution. The propositus fits the histopathology of FFI with similar clinical duration and confirms the role of disease duration in determining histopathology and PrP(res) distribution in FFI.

Age of Onset↗
PubMed1997

Biopsy diagnosis of Creutzfeldt-Jakob disease by western blot: a case report.

Creutzfeldt-Jakob disease is a clinically and pathologically heterogeneous disorder that often requires brain biopsy for definitive diagnosis. We report the case of a 62-year-old man who underwent brain biopsy for progressive neurological deterioration. Histopathologically, there was minimal spongiform change that could not be unequivocally attributed to Creutzfeldt-Jakob disease. A 16 mg portion of gray matter saved frozen was subsequently analyzed by Western blot and showed definitive protease-resistant prion protein. This case illustrates applicability, ease in interpretation, and accuracy of Western blot analysis for protease-resistant prion protein in small brain biopsy specimens. Given the importance of accurate diagnosis in suspected prion disease, we recommend that a small portion of tissue from any brain biopsy performed in this setting be kept frozen for possible biochemical studies.

Biopsy↗
PubMed1997

Allelic origin of the abnormal prion protein isoform in familial prion diseases.

The hallmark of prion diseases is the presence of an aberrant isoform of the prion protein (PrP(res)) that is insoluble in nondenaturing detergents and resistant to proteases. We investigated the allelic origin of PrP(res) in brains of subjects heterozygous for the D178N mutation linked to fatal familial insomnia (FFI) and a subtype of Creutzfeldt-Jakob disease (CJD178), as well as for insertional mutations associated with another CJD subtype. We found that in FFI and CJD178 subjects, only mutant PrP was detergent-insoluble and protease-resistant. Therefore, PrP(res) derives exclusively from the mutant allele carrying the D178N mutation. In contrast, in the CJD subtype harboring insertional mutations, wild-type PrP was also detergent-insoluble and likely to be protease-resistant. Our findings indicate that the participation of the wild-type PrP in the formation of PrP(res) depends on the type of mutations, providing an insight into the molecular mechanisms underlying the phenotypic heterogeneity in familial prion diseases.

Alleles↗
PubMed1997

Power spectral analysis of heart rate and diastolic blood pressure variability in migraine with and without aura.

Autonomic function in migraineurs during headache-free periods was studied by means of cardiovascular reflexes and power spectral analysis of heart rate and diastolic blood pressure variability. We examined 56 patients: 37 suffering from migraine without aura and 19 from migraine with aura. Cardiovascular responses to the tilt test and Valsalva manoeuvre showed a normal function of the overall baroreceptor reflex arc. Normal heart rate responses to Valsalva manoeuvre and deep breathing suggested an intact parasympathetic function. Power spectral analysis of both heart rate and diastolic blood pressure variability in basal conditions and during orthostatic test showed similar sympathovagal interactions modulating cardiovascular control in migraine patients and in controls.

Adult↗
PubMed1997

Cerebral metabolism in fatal familial insomnia: relation to duration, neuropathology, and distribution of protease-resistant prion protein.

We used [18F]-2-fluoro-2-deoxy-D-glucose (FDG) and PET to study regional cerebral glucose utilization in seven patients with fatal familial insomnia (FFI), an inherited prion disease with a mutation at codon 178 of the prion protein gene. Four patients were methionine/methionine homozygotes at codon 129 (symptom duration, 8.5 +/- 1 months) and three were methionine/valine (MET/VAL129) heterozygotes (symptom duration, 35 +/- 11 months). A severely reduced glucose utilization of the thalamus and a mild hypometabolism of the cingulate cortex were found in all FFI patients. In six subjects the brain hypometabolism also affected the basal and lateral frontal cortex, the caudate nucleus, and the middle and inferior temporal cortex. Comparison between homozygous or heterozygous patients at codon 129 showed that the hypometabolism was more widespread in the MET/VAL129 group, which had a significantly longer symptom duration at the time of [18F] FDG PET study. Comparison between neuropathologic and [18F] FDG PET findings in six patients showed that areas with neuronal loss were also hypometabolic. However, cerebral hypometabolism was more widespread than the histopathologic changes and significantly correlated with the presence of protease-resistant prion protein (PrPres). Our findings indicate that hypometabolism of the thalamus and cingulate cortex is the hallmark of FFI, while the involvement of other brain regions depends on the duration of symptoms and some unknown factors specific to each patient. The present data also support the notion that PrPres formation is the cause of neuronal dysfunction in prion diseases.

Adult↗
PubMed1997

Familial prion disease with a novel 144-bp insertion in the prion protein gene in a Basque family.

Three members of a Basque family carrying a novel six R2 octapeptide repeat 144-bp insertion in the prion protein gene (PRNP) showed a slowly progressive dementia associated with cerebellar signs, myoclonic jerks, and seizures. Although postmortem examination revealed only focal and minimal spongiform degeneration in one subject with a 4-year course, significant astrogliosis and neuronal loss were associated with pronounced spongiform degeneration in the patient with a duration of symptoms of 10 years. Prion protein (PrP)-immunoreactive patches with a unique morphology were present in the molecular layer of the cerebellum in both subjects. Western blot analysis demonstrated the presence of protease-resistant prion protein (PrPres) with the same characteristics (size and ratio of the three differently glycosylated isoforms) of that found in typical sporadic Creutzfeldt-Jakob disease (CJD129M/M, PrPres type 1). The amount of PrPres correlated with presence and severity of spongiform degeneration in the cerebral cortex. The findings suggest that a relatively low rate of PrPres deposition is the cause of the lack of spongiform degeneration in subjects carrying a 144-bp insertion in PRNP. The presence of PrP-immunoreactive patches with unique morphology in the molecular layer of the cerebellum is a hallmark of certain prion encephalopathies with insertional mutations and is useful in the diagnosis of this subtype of human prion disease.

Adult↗
PubMed1996

Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity.

The fundamental event in prion diseases seems to be a conformational change in cellular prion protein (PrPC) whereby it is converted into the pathologic isoform PrPSc. In fatal familial insomnia (FFI), the protease-resistant fragment of PrPSc after deglycosylation has a size of 19 kilodaltons, whereas that from other inherited and sporadic prion diseases is 21 kilodaltons. Extracts from the brains of FFI patients transmitted disease to transgenic mice expressing a chimeric human-mouse PrP gene about 200 days after inoculation and induced formation of the 19-kilodalton PrPSc fragment, whereas extracts from the brains of familial and sporadic Creutzfeldt-Jakob disease patients produced the 21-kilodalton PrPSc fragment in these mice. The results presented indicate that the conformation of PrPSc functions as a template in directing the formation of nascent PrPSc and suggest a mechanism to explain strains of prions where diversity is encrypted in the conformation of PrPSc.

Animals↗
PubMed1996

Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion protein.

Prion diseases are thought to be caused by the conversion of the normal, or cellular, prion protein (PrPC)(PrPres). There are three familial forms of human prion disease, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia (FFI) which are all expressed at advanced age despite the congenital presence of the mutant prion protein (PrPM). The cellular mechanisms that result in the age-dependent conversion of PrPM into PrPres and the unique phenotypes associated with each PrPM are unknown. FFI and a familial type of Creutzfeldt-Jakob disease (CJD178), share the D178N mutation in the PrP gene but have distinct phenotypes linked to codon 129, the site of a methionine/valine polymorphism (129M/V). We analyzed PrP processing in cells transfected with constructs reproducing the FFI and CJD178 genotypes. The D178N mutation results in instability of the mutant PrP which is partially corrected by N-glycosylation. Hence, only the glycosylated forms of PrPM reach the cell surface whereas the unglycosylated PrPM is also under-represented in the brain of FFI patients validating the cell model. These results offer new insight into the effect of the D178N mutation on the metabolism of the prion protein.

Base Sequence↗
PubMed1996

The neuropathology of chromosome 17-linked dementia.

We recently described a family with chromosome 17-linked dementia, characterized clinically by disinhibition-dementia-parkinsonism-amyotrophy complex. We report now the neuropathology of 6 affected family members. This included semiquantitative scoring of neuronal loss, gliosis, and spongiosis and immunocytochemical and ultrastructural characterization of neuronal and glial inclusions. The changes consisted of circumscribed neuronal loss, gliosis, and spongiosis of limbic neocortical areas and frontal, temporal, and occipital association areas. Similar changes were present in subcortical nuclei, most severe in the substantia nigra, but also involved the ventral striatum and amygdala. The hippocampus was spared except for degeneration of the afferent perforant tract, secondary to entorhinal nerve cell loss. Argyrophilic neuronal inclusions, with a characteristic immunocytochemical profile, were found in brainstem nuclei, hypothalamus and basal ganglia. Ultrastructurally, in 3 patients these inclusions showed hitherto undescribed abnormally assembled filaments. Glial cytoplasmic inclusions were widespread in white matter structures. Immunocytochemistry failed to demonstrate the protease-resistant prion protein. The pathology appears to be unique, involving various cortical and subcortical structures, and is consistent with the clinical findings of Kluver-Bucy-like syndrome, parkinsonism, and frontal lobe dementia. For this entity we suggest the term "chromosome 17-linked dementia."

Brain↗
PubMed1996

Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease.

We sequenced the prion protein gene and studied the biochemical characteristics and the intracerebral distribution of protease-resistant prion protein with Western blot and immunohistochemistry in 19 cases of sporadic Creutzfeldt-Jakob disease. We identified four groups of subjects defined by the genotype at codon 129 of the prion protein gene, the site of a common methionine/valine polymorphism, and two types of protease-resistant prion proteins that differed in size and glycosylation. The four Creutzfeldt-Jakob disease groups showed distinct clinicopathological features that corresponded to previously described variants. The typical Creutzfeldt-Jakob disease phenotype or myoclonic variant and the Heidenhain variant were linked to methionine homozygosity at codon 129 and to "type 1" protease-resistant prion protein. The atypical and rarer variants such as that with dementia of long duration, the ataxic variant, and the variant with kuru plaques were linked to different genotypes at codon 129 and shared the "type 2" protease-resistant prion protein. Our data indicate that the sporadic form of Creutzfeldt-Jakob disease comprises a limited number of variants. The methionine/valine polymorphism at codon 129 of the prion protein gene and two types of protease-resistant prion proteins are the major determinants of these variants. These findings suggest the existence of prion strains in humans and provide the molecular basis for a novel classification of sporadic Creutzfeldt-Jakob disease.

Adult↗
PubMed1996

Early pathologic and biochemical changes in Creutzfeldt-Jakob disease: study of brain biopsies.

We examined brain biopsy tissue from five patients with a neurologic syndrome consistent with Creutzfeldt-Jakob disease using Western blot analysis and immunohistochemistry for the detection of protease-resistant prion protein, in addition to histopathologic examination. Our results indicate that the formation of protease-resistant prion protein is an early event in disease pathogenesis and Western blot analysis can detect protease-resistant prion protein in the absence of structural lesions using a small amount of brain biopsy tissue.

Adult↗