Typical Creutzfeldt-Jakob Disease Research Articles

Clinical Features and Diagnosis of the MM2 Cortical Subtype of Sporadic Creutzfeldt-Jakob Disease

To describe clinical features and diagnostic tests of the MM2 cortical subtype in sporadic Creutzfeldt-Jakob disease. Clinical symptoms, magnetic resonance imaging studies, electroencephalograms, and cerebrospinal fluid markers were studied in 12 patients with genetically and neuropathologically verified sporadic Creutzfeldt-Jakob disease. Histological findings were semiquantitatively evaluated. Compared with classical sporadic Creutzfeldt-Jakob disease, the disease duration was prolonged (median, 14 months). All patients had dementia and early and prominent neuropsychological signs such as spatial disorientation, aphasia, or apraxia. Alzheimer disease was the most frequent initial diagnosis (33%). Increased S100B protein in the cerebrospinal fluid was found in 100%; the 14-3-3 protein test was positive in 91%. Electroencephalograms revealed periodic sharp wave complexes in 42%. T2-weighted magnetic resonance imaging showed basal ganglia hyperintensities in only 1 patient, and cortical hyperintensities were not necessarily present. Severe cortical damage was the most prominent histological feature. The S100B (100%) and 14-3-3 (91%) protein investigations were the most sensitive diagnostic tests. Prolonged disease duration, dementia as the only typical Creutzfeldt-Jakob disease symptom for a longer time, and low sensitivity of magnetic resonance imaging studies and electroencephalograms make the diagnosis in the MM2 cortical subtype difficult. Therefore, detailed clinical investigation is especially important in this sporadic Creutzfeldt-Jakob disease subtype. We suggest that rapidly progressive dementia with early and prominent neuropsychological deficits in older patients should lead to suspicion of the MM2 cortical subtype even if other neurological deficits are absent. At least some cases of MM2 cortical sporadic Creutzfeldt-Jakob disease may be misdiagnosed as rapidly progressive Alzheimer disease.

Coexistence of multiple PrP Sc types in individuals with Creutzfeldt-Jakob disease

The molecular typing of sporadic Creutzfeldt-Jakob disease (CJD) is based on the size and glycoform ratio of protease-resistant prion protein (PrP(Sc)), and on PRNP haplotype. On digestion with proteinase K, type 1 and type 2 PrP(Sc) display unglycosylated core fragments of 21 kDa and 19 kDa, resulting from cleavage around amino acids 82 and 97, respectively. We generated anti-PrP monoclonal antibodies to epitopes immediately preceding the differential proteinase K cleavage sites. These antibodies, which were designated POM2 and POM12, recognise type 1, but not type 2, PrP(Sc). We studied 114 brain samples from 70 patients with sporadic CJD and three patients with variant CJD. Every patient classified as CJD type 2, and all variant CJD patients, showed POM2/POM12 reactivity in the cerebellum and other PrP(Sc)-rich brain areas, with a typical PrP(Sc) type 1 migration pattern. The regular coexistence of multiple PrP(Sc) types in patients with CJD casts doubts on the validity of electrophoretic PrP(Sc) mobilities as surrogates for prion strains, and questions the rational basis of current CJD classifications.

Prion protein accumulation in eyes of patients with sporadic and variant Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) primarily affects the brain. This study was conducted to assess the possible involvement of the eye in sporadic and variant CJD by testing for the presence of the disease-associated, protease-resistant isoform of the prion protein (PrP(Sc)) in ocular tissue. Human eyes from donors with CJD and non-prion neurodegenerative disease control eyes were studied. In situ hybridization and Western blot analysis were used to determine the normal pattern of cellular prion protein (PrP(C)) expression. Western blot analysis and immunohistochemistry were then used to determine the localization, abundance, and isotype of PrP(Sc) in eyes in CJD. PrP(C) was expressed in the nuclear layers of the retina. In both the sporadic and variant forms of CJD, PrP(Sc) accumulated throughout the synaptic layers of the retina. The levels of PrP(Sc) found in the retina were comparable with those found in the brain. Lower levels of PrP(Sc) could be found in the optic nerve, but no PrP(Sc) was detectable in other ocular tissues. The glycoform ratio of PrP(Sc) in the retina did not correspond to that found in the brain. Presumptive centrifugal spread of PrP(Sc) from the brain through the optic nerve occurs in two major types of CJD. PrP(Sc) is a marker of CJD infectivity. Given that routine decontamination may not remove PrP(Sc) from surgical instruments, a careful risk assessment should be made of possible iatrogenic spread of sporadic and variant CJD after surgery to the retina or optic nerve.

BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein.

Variant Creutzfeldt-Jakob disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrP(Sc) type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a disease arising from BSE exposure.

Rapid Genotyping of the M129V Polymorphism of Prion Protein Using Real-Time Fluorescent PCR

The human prion diseases are fatal neurodegenerative disorders that may present as sporadic, hereditary, or infectious processes. The most common is the sporadic form associated with a typical Creutzfeldt-Jakob disease (CJD) phenotype; heritable forms may have, in addition to a CJD phenotype, Gerstmann-Straussler-Scheinker or fatal familiar insomnia phenotypes. The infectious forms may occur as CJD or kuru. It has been proposed that the codon 129 polymorphism in the prion protein gene ( PRNP ) is largely correlated with phenotype heterogeneity of these diseases (1). This correlation has suggested the use of the polymorphism in the clinicopathologic classification of the sporadic CJD (2). Recently, a novel form of human prion disease (nvCJD) that is thought to be linked with bovine spongiform encephalopathy has been described. Almost all cases of nvCJD with available genetic analysis were methionine homozygotes at codon 129 of …

Creutzfeldt–Jakob disease with a novel four extra-repeat insertional mutation in the PrP gene

To investigate the role of a short insertional mutation in the prion protein (PrP) gene (PRNP) in prion disease pathogenesis. The genetic forms of Creutzfeldt-Jakob disease (CJD) are associated with point or insertional mutations in PRNP. Whereas patients with five, six, seven, eight, and nine extra octapeptide repeats show an autosomal dominant pattern of inheritance and features of CJD, Gerstmann-Sträussler-Scheinker disease, or atypical dementia, patients with one, two, or four extra repeats have typical CJD and lack a family history of neurologic disorder. A genetic, neuropathologic, and biochemical study was carried out in a 65-year-old patient with clinical features of sporadic CJD. A novel four extra-repeat insertional mutation of PRNP was found in the patient and in his 59-year-old healthy sister. The patient showed spongiosis, nerve cell loss, and gliosis associated with diffuse PrP immunoreactivity in the cerebral cortex, subcortical gray structures, and cerebellum. A peculiar aspect was the presence of focal PrP deposits in the basal ganglia and hypothalamus, superimposed to diffuse PrP immunoreactivity. The biochemical analysis revealed that both mutant and wild-type PrP participated in the pathologic process, and that the protease-resistant core of the altered PrP isoforms was distinct from that observed in sporadic, acquired, and other genetic forms of CJD. These findings support the view that the four extra-repeat insertion in PRNP is a pathogenic mutation with low penetrance rather than a benign polymorphism, and suggest that this mutation results in the formation of a distinct PrP conformer.

Bilaterale inferiore Hemianopsie als Frühsymptom einer Creutzfeldt-Jakob-Erkrankung vom Heidenhain-Typ12

The Heidenhain variant is a subtype of Creutzfeldt-Jakob disease (CJD) where visual symptoms are leading. We report on a 60-year-old woman who developed within a few weeks bilateral inferior hemianopsia. Morphological findings of the eyes were normal. Neurological examination and cerebral CT/MRI were normal too. P 100 latency of visual evoked potentials (VEP) of both eyes, however, was delayed. During the course of the disease visual field narrowed progressively and 3 months after the first symptoms the patient went blind. Only at that time myoclonia, hyperkinesia, and psychiatric symptoms appeared. Changes of EEG and cerebrospinal fluid were suggestive of Creutzfeldt-Jakob disease (CJD). The patient died after 5 1/2 months and diagnosis was confirmed neuropathologically with mainly occipital spongiform encephalopathy. This case illustrates the diagnostic difficulties of the Heidenhain type of CJD and demonstrates that in patients with progressive visual field defects without morphological abnormalities of the eyes or radiological abnormalities of the brain CJD should be considered. It should be looked out for additional neurological (especially extrapyramidal) and psychiatric symptoms.

Biochemical and conformational variability of human prion strains in sporadic Creutzfeldt–Jakob disease

The pathogenesis of prion (PrP) diseases is thought to be related to conformational changes of a normal cellular protein, PrP C, into a protease resistant protein called PrP Sc, which is infectious by itself. A difficulty with this ‘protein only’ hypothesis is the existence of numerous PrP strains, that require PrP Sc to have multiple conformations. Sporadic Creutzfeldt–Jakob disease (CJD), which accounts for nearly 80% of human prionoses, was reported to include at least two ‘strains’ termed types 1 and 2 which differ by electrophoretic patterns of their proteinase K (PK)-resistant fragments (PrP27–30). We have analyzed the biochemical and structural properties of PrP Sc and PrP27–30 isolates from six sporadic CJD patients. Fourier transform-infra-red spectroscopy, PrP27–30 glycosylation patterns and studies of PK sensitivity revealed a striking heterogeneity. Furthermore, one isolate yielded a PrP27–30 fragment with a lower mobility clearly different from previously described sporadic CJD types. Although the average β-sheet content was higher among type 1 isolates, there was overlap between the two types. Our study suggests that human sporadic CJD-related prions display a significant heterogeneity.

Les maladies à prions en pédiatrie

Prion diseases are rare neurologic affections with a poor prognosis, occurring in both humans and animals. Creutzfeldt-Jakob disease (CJD) secondary to human extracted growth hormone treatment is the most frequent condition in pediatrics. In 1994, a new type of CJD (variant CJD) was described in young adults in the United Kingdom, only 10 years after the bovine spongiform encephalopathy epidemic, with recent works showing a direct relationship between the bovine epidemic and the human cases. An accumulation of a single protein called the prion protein (PrP) has been discovered in the brain in all of these cases, animal and human, leading to the hypothesis that a new infectious agent could proceed without any nuclear acid information; another hypothesis is that of a still unknown viral agent. The PRNP gene encoding for this PrP protein is well described: some mutations and a polymorphism in the 129th codon have been shown to be implicated in many cases of CJD. PrP is a ubiquitous protein, with yet unknown physiological function. There are still many questions to be answered: shall we expect new pediatric cases of variant CJD? Assuming that animal-human contamination is related to alimentation, are there other ways of contamination.

Molecular analysis of prion protein gene (PRNP) in Korean patients with Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD), a relatively uncommon human dementia, is caused by an unconventional slow infectious agent. Several cases of CJD, clinically or histopathologically diagnosed, have been reported in Korea. In order to confirm the diagnosis of CJD and also differential diagnosis of sporadic and familial types of CJD in Korea, we studied two patients who had symptoms of CJD. The histopathological and immunohistochemical studies showed spongiform neurodegeneration and expression of abnormal isoform of prion protein (PrPSc) in astrocytes. Thus, these two patients were diagnosed CJD. To investigate whether these patients were sporadic or familial type of CJD, the molecular analyses of the prion protein gene (PRNP) were done by restriction fragment length polymorphism (RFLP) and DNA sequencing. In the cases of a healthy Korean and two CJD patients, no point mutation was detected in the known hot spots (178, 180, 200, 210, and 232) and they exhibited wild type PRNP sequences. We concluded that both patients have a sporadic type of CJD, but not familial type.

Anesthesia and non-conventional transmissible agents (or prion diseases)

The transmissible spongiform encephalopathies (TSE) represent a group of neurodegenerative diseases with lethal outcome. They include Creutzfeldt-Jakob disease (CJD) and kuru, among others in humans, scrapie in sheep and spongiform encephalopathy in cattle (bovine spongiform encephalopathy: BSE). Some are autosomal dominant disorders like CJD, Gerstmann-Straüssler-Scheinker disease (GSS), with point mutation of the prion protein gene. Most of these diseases are idiopathic rather than sporadic, latrogenic CJD could be obtained by central inoculation (neurosurgical instruments or dura mater grafts) or by peripheral inoculation (pituitary hormone therapy). A new variant clinicopathological type of CJD (nvCJD) has been reported. The nvCJD has strain characteristics distinct from other types of CJD, close to those of BSE transmitted (studies with intracerebral inoculation), consistent with BSE being the source of this new disease. All of these spongiform encephalopathies (SE) are characterized by spongiform degeneration of the brain, reactive gliosis in the cortical and subcortical gray matter, neuronal loss and presence of the abnormal isoform of the cellular prion protein (PrPc). In prion disease, PrPc undergoes conformational changes involving a shift from alpha-helix to beta-sheet structure. These neurologic lesions are characterized by major variations from case to case. Neuropathological studies in sporadic CDJ have emphasized phenotypic variations. Clinical presentation with a wide spectrum of manifestations is a rapidly progressive dementia, associated with myoclonus or akinetic mutism and cortical blindness. The clinical course is atypical and when the characteristic triphasic abnormal EEG of CJD is absent, there is an urgent need for a premortem diagnostic test. Histopathological examination of a brain biopsy carries a risk of major morbidity and may miss the site of disease. The 14-3-3 immunoassay of cerebrospinal fluid strongly supports a diagnosis of CJD. Western blot analysis of human tonsil biopsy may allow an early or preclinical diagnosis. It has been suggested that CJD might be transmitted by blood products derived from patients with CJD during the prodromal stage, although CJD linked aetiologically to blood transfusion has not been demonstrated. In animal studies, intracerebral inoculation of infected cells has been associated with development of disease, but never after peripheral inoculation into the blood stream. For the most part of conformational changes of PrPc, the remarkable resistance of the infectious agent (PrP alone or combined) to ordinary sterilising procedures is a major problem. Because of this resistance, current recommendations are to recognize patients at risks and to use disposable medical devices. This is particularly true in anaesthesia during endotracheal intubation, spinal anaesthesia, and to a lesser extent with peripheral nerve blocks. All instruments used for patients with CJD must be destroyed. The economic consequences of these measures have highlighted the essential importance of an early diagnosis.

Diagnosis of Creutzfeldt-Jakob disease and related human spongiform encephalopathies

Spongiform encephalopathies are transmissible diseases (TSE) of animals and humans. With the appearance of bovine spongiform encephalopathy (BSE) in 1986 and in 1996 with the identification of an apparently new variant of the human spongiform encephalopathy Creutzfeldt-Jakob disease (CJD), great concerns of a potential transmission of BSE to humans have been voiced. The agent known to transmit CJD and other human and animal spongiform encephalopathies is designated as prion, i.e., proteinaceous infectious agent, due to the absence of evidence for the involvement of a nucleic acid in disease transmission. In humans the clinical diagnosis of typical CJD cases can now be supported by paraclinical parameters. Electroencephalographic changes, so called periodic sharp wave complexes, are pathognomonic for CJD but by no means specific. The detection of neuronal enzymes in the cerebrospinal fluid (CSF) such as neuron specific enolase (NSE) or glial proteins such as S-100 aids greatly in the diagnosis of a human spongiform encephalopathy. By far the most specific marker in CSF are a group of proteins designated 14-3-3. Current evidence suggests that by including elevated levels of NSE (> or = 35 ng/mL), S-100 (> or = 8 ng/mL) and tau protein in the CSF and the presence of 14-3-3, a laboratory supported diagnosis of CJD can be achieved which in the appropriate clinical setting has a better diagnostic accuracy than the currently used clinical and paraclinical diagnostic criteria alone.

Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD.

Strains of transmissible spongiform encephalopathies are distinguished by differing physicochemical properties of PrPSc, the disease-related isoform of prion protein, which can be maintained on transmission to transgenic mice. 'New variant' Creutzfeldt-Jakob disease (CJD) has strain characteristics distinct from other types of CJD and which resemble those of BSE transmitted to mice, domestic cat and macaque, consistent with BSE being the source of this new disease. Strain characteristics revealed here suggest that the prion protein may itself encode disease phenotype.

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.

Tumor necrosis factor alpha (TNF-α) is involved in the pathogenesis of the panencephalopathic type of Creutzfeldt-Jakob disease

Tumor necrosis factor alpha (TNF-α) is involved in the pathogenesis of the panencephalopathic type of Creutzfeldt-Jakob disease

Further ultrastructural studies of lesions produced in the optic nerve by Tumor necrosis factor alpha (TNF-alpha): a comparison with experimental Creutzfeldt-Jakob disease

We report here that intraocular injection of recombinant TNF-alpha produces lesions in the optic nerve indistinguishable from those reported for the panencephalopathic type of Creutzfeldt-Jakob disease (CJD). The lesions were patchy and confined to the injected optic nerve. Axons show variable features of degenerations. Numerous vacuoles distended the myelin sheath. Hypetrophic astrocytes were numerous and many active macrophages containing digested myelin debris and lyre-like paracrystalline bodies. At high power, myelinated axons were observed as enveloped by astrocytic processes; formation of labyrinth-like network of such processes around damaged axons were observed. In conclusions, lesions produced by TNF-alpha mimic those of the panencephalopathic type of CJD, in direct support of our previous ultrastructural, immunohistochemical and molecular data on TNF-alpha involvement in CJD pathogenesis.

CT Appearance of Panencephalopathic and Ataxic Type of Creutzfeldt-Jakob Disease

We present a proven case of Creutzfeldt-Jakob disease with severe involvement of white matter and cerebellum. Serial CT showed a unique pattern consisting of discrete cerebral and cerebellar atrophy, diffuse white matter hypodensity, and progressive enlargement of lateral and fourth ventricles.

Swollen Cortical Neurons in Creutzfeldt-Jakob Disease Contain a Phosphorylated Neurofilament Epitope

The distribution of swollen neurons and the presence of a phosphorylated neurofilament protein (NFP) epitope in these cells were studied in six cases of Creutzfeldt-Jakob disease (CJD). Swollen neurons are widely distributed in the cerebral cortex and are most abundant in the cingulate and parahippocampal gyri. They are more numerous in the panencephalopathic type of CJD than in the subacute spongiform encephalopathic type. A phosphorylated epitope of NFP was detected in the perikarya of swollen neurons by an immunocytochemical method using a series of monoclonal antibodies that distinguish phosphorylated and nonphosphorylated epitopes of NFP. This abnormal distribution of phosphorylated NFP epitopes indicates that the process of NFP phosphorylation is altered in neurons affected by CJD. This investigation, in accordance with previous studies, suggests that the abnormal post-translational modification of the neurofilament may play an important role in the pathogenesis of several neurodegenerative disorders.

White matter ultrastructural pathology of experimental Creutzfeldt-Jakob disease in mice

Creutzfeldt-Jakob disease (CJD), previously regarded as a neurodegenerative disorder strictly of the gray matter, occasionally occurs as a panencephalopathic form which is characterized by severe white matter damage. An ultrastructural study of the white matter pathology in mice experimentally infected with the Fujisaki strain of CJD virus revealed: (1) vacuoles within myelin sheaths, formed by splitting either at the major dense or intraperiod lines, or within axons; (2) macrophages filled with numerous myelin figures, lipid droplets and paracrystalline inclusions; (3) astrocytes actively digesting myelin debris; (4) unusual wrapping of several axons by a common myelin sheath; (5) vesicular degeneration of myelin sheaths; (6) close contact between numerous coated pits and outer myelin lamellae; and (7) proliferation of inner mesaxons. Our data indicate that the damage to myelinated axons in the panencephalopathic type of CJD is accomplished primarily by active degradation of myelin by macrophages and astrocytes and by formation of intra-axonal and intra-myelin vacuoles. The myelin vacuolation is most consistent with that produced by leukolysins released from activated macrophages and astrocytes.

Panencephalopathic type of Creutzfeldt-Jakob disease: primary involvement of the cerebral white matter.

Eight necropsy cases of a "panencephalopathic" type of Creutzfeldt-Jakob disease (CJD) in the Japanese are reported. The reasons why this type should be discussed separately from other types of CJD are that there is primary involvement of the cerebral white matter as well as the cerebral cortex, and that the white matter lesion of one Japanese human brain with CJD similar to the present group has been successfully transmitted to experimental animals.