ABSTRACT
Fatal insomnia is a rare human prion disease characterised by sleep-wake disturbances, thalamic degeneration and deposition of type 2 disease-specific prion protein (PrP(Sc)). This report details a patient with sporadic fatal insomnia who exhibited cerebral deposition of type 1 PrP(Sc) and neuropathological changes largely in the basal ganglia. Previous damage of this brain region by a surgically removed colloid cyst and the insertion of two intracerebral shunts may have influenced the distribution of PrP(Sc) through a chronic inflammatory process. These findings add to our knowledge of the phenotypic variability of human prion diseases with prominent sleep disturbances.
Subject(s)
Insomnia, Fatal Familial/pathology , PrPSc Proteins/metabolism , Blotting, Western , Brain/pathology , Creutzfeldt-Jakob Syndrome/pathology , Electroencephalography , Humans , Immunohistochemistry , Insomnia, Fatal Familial/genetics , Insomnia, Fatal Familial/metabolism , Magnetic Resonance Imaging , Male , Middle Aged , Neurosurgical Procedures , PrPSc Proteins/genetics , Tomography, X-Ray ComputedABSTRACT
Cerebral accumulation of hyperphosphorylated tau (phospho-tau) occurs in several neurodegenerative conditions including Alzheimer disease. In prion diseases, phospho-tau deposition has been described in a rare genetic form, Gerstmann-Sträussler-Scheinker disease, but is not considered part of the neuropathological picture of Creutzfeldt-Jakob disease. Aim of this study was to investigate whether changes related to phospho-tau accumulation are present in the brain of patients with variant Creutzfeldt-Jakob disease (vCJD) that shares with Gerstmann-Sträussler-Scheinker disease abundant prion protein (PrP) deposition in amyloid form. The analysis was extended to experimental mouse models of vCJD. We detected a large number of phospho-tau-immunoreactive neuritic profiles, often clustered around PrP amyloid deposits, not only in the cerebral cortex, but also in the cerebellum of all vCJD patients examined, in the absence of Abeta. Although less constantly, phospho-tau was localized in some perikaria and dendrites. The biochemical counterpart was the presence of phospho-tau in the detergent-insoluble fraction of cerebral cortex. Phospho-tau-immunoreactive neuronal profiles were also found in association with PrP deposits in mouse models of vCJD. These findings suggest that the abnormal forms of PrP associated with vCJD trigger a tauopathy, and provide a paradigm for the early stages of tau pathology associated with cerebral amyloidoses, including Alzheimer disease.
Subject(s)
Cerebellum/metabolism , Cerebral Cortex/metabolism , Creutzfeldt-Jakob Syndrome/metabolism , Disease Models, Animal , tau Proteins/metabolism , Adult , Animals , Female , Humans , Male , Mice , Mice, Inbred C57BL , Middle Aged , Tissue DistributionABSTRACT
An atypical case of sporadic Creutzfeldt-Jakob disease (CJD) is described in a 78-year-old woman homozygous for methionine at codon 129 of the prion protein (PrP) gene. The neuropathological signature was the presence of PrP immunoreactive plaque-like deposits in the cerebral cortex, striatum and thalamus. Western blot analysis showed a profile of the pathological form of PrP (PrP(Sc)) previously unrecognised in sporadic CJD, marked by the absence of diglycosylated protease resistant species. These features define a novel neuropathological and molecular CJD phenotype.
Subject(s)
Creutzfeldt-Jakob Syndrome/genetics , PrPSc Proteins/genetics , Aged , Antibodies/immunology , Antibodies, Monoclonal/immunology , Antiparkinson Agents/therapeutic use , Blotting, Western , Brain/immunology , Brain/pathology , Codon/genetics , Creutzfeldt-Jakob Syndrome/diagnosis , Creutzfeldt-Jakob Syndrome/immunology , Female , Humans , Immunohistochemistry , Levodopa/therapeutic use , Magnetic Resonance Imaging , Methionine/genetics , Parkinsonian Disorders/drug therapy , Phenotype , Polymorphism, Genetic/genetics , PrPSc Proteins/immunology , Valine/geneticsABSTRACT
Three members of an Italian family with autosomal dominant dementia and multiple strokes had the A713T mutation of the APP gene. The neuropathologic examination of the proband disclosed Alzheimer disease (AD) with severe cerebral amyloid angiopathy and multiple infarcts. This indicates that the A713T mutation of the APP gene, lying at the gamma-secretase cleavage site, can be responsible for AD with symptomatic cerebral amyloid angiopathy.
Subject(s)
Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Cerebral Amyloid Angiopathy/genetics , Cerebral Infarction/genetics , Mutation, Missense , Point Mutation , Alzheimer Disease/pathology , Amino Acid Substitution , Amyloid Precursor Protein Secretases , Amyloid beta-Protein Precursor/chemistry , Aspartic Acid Endopeptidases , Brain/pathology , Cerebral Amyloid Angiopathy/pathology , Cerebral Infarction/pathology , Codon/genetics , DNA Mutational Analysis , Disease Progression , Endopeptidases/metabolism , Female , Genes, Dominant , Humans , Italy , Magnetic Resonance Imaging , Male , Middle Aged , PedigreeABSTRACT
The authors investigated two unrelated patients with Creutzfeldt-Jakob disease (CJD) with clinical features of sporadic CJD (sCJD) carrying one extra octapeptide repeat in the prion protein (PrP) gene (PRNP). A synaptic type PrP distribution throughout the cerebral gray matter and plaque-like PrP deposits in the subcortical gray structures were detected immunocytochemically. The different patterns of PrP deposition were associated with distinct types of protease-resistant PrP, similar to type 1 and type 2 of sCJD. The features suggest that this insertion is a pathogenic mutation.
Subject(s)
Amyloid/genetics , Creutzfeldt-Jakob Syndrome/genetics , Prions/genetics , Protein Precursors/genetics , 14-3-3 Proteins , Brain/pathology , Brain Chemistry , Creutzfeldt-Jakob Syndrome/cerebrospinal fluid , Creutzfeldt-Jakob Syndrome/diagnosis , Electroencephalography , Endopeptidases/chemistry , Heterozygote , Homozygote , Humans , Immunoblotting , Immunohistochemistry , Male , Middle Aged , Mutation , Polymerase Chain Reaction , Prion Proteins , Prions/chemistry , Tyrosine 3-Monooxygenase/cerebrospinal fluid , tau Proteins/cerebrospinal fluidABSTRACT
Workers' compensation costs for management of soft tissue disorders continue to increase. The complexity of medical management of these cases has increased due to social factors. The purpose of this study is to improve the physician's ability to recognize nonmedical issues that prevent a rapid return to employment. A classification system is presented that will allow the clinician to identify administrative and pyschosocial issues that prolong disability. Additionally, the patients' job demands were classified by known ergonomic risk factors. The system was applied retrospectively to 50 random cases referred to two occupational hand clinics over a 1-year period. The results indicated that the psychosocial classification of the patient and the current employment status are the most important factors in prolonging disability workers.
