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  1. Creutzfeldt-Jakob Disease

    MedlinePlus

    Creutzfeldt-Jakob disease (CJD) is a rare, degenerative brain disorder. Symptoms usually start around age 60. Memory problems, behavior changes, vision ... during a medical procedure Cattle can get a disease related to CJD called bovine spongiform encephalopathy (BSE) ...

  2. Creutzfeldt-Jakob disease.

    PubMed

    de Villemeur, Thierry Billette

    2013-01-01

    Prion diseases are rare in children. Three types are known: kuru, variant Creutzfeldt-Jakob disease (CJD), and iatrogenic CJD. All three affect children and young adults, and are transmitted by infectious contamination. Kuru was the result of ritual funeral practices similar to cannibalism; variant CJD affects young people who have eaten meat from cows with mad cow disease (mostly in the UK); and iatrogenic CJD is secondary to graft of human tissues performed in the 1980s (dura mater, pituitary extracted growth hormone). The disease appears after 4-30 years of incubation. The initial symptomatology is frequently neurological (cerebellar ataxia, oculomotor disturbance, peripheral nerve pain, pyramidal syndrome) followed by dementia. There is no biological test available that can give a definite diagnosis of prion disease apart from neuropathology, although prion accumulation in vCJD can be demonstrated in pharyngeal tonsil by immunohistochemical techniques. This devastating disease results inevitably in death. No specific treatment is available.

  3. Creutzfeldt-Jakob disease.

    PubMed

    Sikorska, Beata; Knight, Richard; Ironside, James W; Liberski, Paweł P

    2012-01-01

    Creutzfeldt-Jakob disease (CJD), a neurodegenerative disorder that is the commonest form of human prion disease or transmissible spongiform encephalopathies (TSEs). Four types of CJD are known: Sporadic (sCJD), familial or genetic (gCJD); iatrogenic (iCJD) and variant CJD (vCJD). The latter results from transmission of bovine spongiform encephalopathy (BSE) from cattle to humans. The combination of PrP(Sc) peptide (either 21 kDa or 19 kDa) and the status of the codon 129 of the gene (PRNP) encoding for PrP (either Methionine or Valine) is used to classify sCJD into 6 types: MM1 and MV1, the most common; VV2; MV2 (Brownell/Oppenheimer syndrome); MM2; VV1 and sporadic fatal insomnia, in that order of prevalence. Genetic CJD is caused by diverse mutations in the PRNP gene. The neuropathology of CJD consists of spongiform change, astro- and microgliosis and poorly defined neuronal loss. In a proportion of cases, amyloid plaques, like those of kuru, are seen. PrP immunohistochemistry reveals different types of PrP(Sc) deposits - the most common is the synaptic-type, but perivacuolar, perineuronal and plaque-like deposits may be also detected.

  4. Creutzfeldt-Jakob disease.

    PubMed

    Iwasaki, Yasushi

    2017-04-01

    This review will explore the clinical and pathological findings of the various forms of Creutzfeldt-Jakob disease (CJD). Clinical findings of CJD are characterized by rapidly progressive cognitive dysfunction, diffusion-weighted magnetic resonance imaging (DWI) hyperintensity, myoclonus, periodic sharp-wave complexes on electroencephalogram and akinetic mutism state. Neuropathologic findings of CJD are characterized by spongiform changes in gray matter, gliosis-particularly hypertrophic astrocytosis-neuropil rarefaction, neuron loss and prion protein (PrP) deposition. The earliest pathological symptom observed by HE staining in the cerebral cortex is spongiform change. This spongiform change begins several months before clinical onset, and is followed by gliosis. Subsequently, neuropil rarefaction appears, followed by neuron loss. Regions showing fine vacuole-type spongiform change reflect synaptic-type PrP deposition and type 1 PrP(Sc) deposition, whereas regions showing large confluent vacuole-type spongiform changes reflect perivacuolar-type PrP deposition and type 2 PrP(Sc) deposition. Hyperintensities of the cerebral gray matter observed in DWI indicate the pathology of the spongiform change in CJD. The cerebral cortical lesions with large confluent vacuoles and type 2 PrP(Sc) show higher brightness and more continuous hyperintensity on DWI than those with fine vacuoles and type 1 PrP(Sc) . CJD cases showing diffuse myelin pallor of cerebral white matter have been described as panencephalopathic-type, and this white matter pathology is mainly due to secondary degeneration caused by cerebral cortical involvement, particularly in regard to neuron loss. In conclusion, clinical and neuroimaging findings and neuropathologic observations are well matched in both typical and atypical cases in CJD. The clinical diagnosis of CJD is relatively easy for typical CJD cases such as the MM1-type. However, even in atypical cases it seems that clinical findings can be used for

  5. Creutzfeldt-Jakob disease

    MedlinePlus

    ... be the same one that causes vCJD in humans. Varient CJD causes less than 1% of all ... Scrapie (found in sheep) Other very rare inherited human diseases, such as Gerstmann-Straussler-Scheinker disease and ...

  6. Creutzfeldt-Jakob Disease

    MedlinePlus

    ... Ping Lu Validation of cis-Tau as a Therapeutic Target for Alzheimer's Disease 2014 Tsuneya Ikezu Exosome Pathway as a ... 2010 Marco Prado The Prion Protein as a Therapeutic Target in Alzheimer's Disease 2007 Michael Vitek Novel Therapeutic Reduces Abeta ...

  7. Creutzfeldt-Jakob disease: implications for gastroenterology.

    PubMed

    Bramble, M G; Ironside, J W

    2002-06-01

    The current clinical views regarding variant Creutzfeldt-Jakob disease, and in particular transmission via endoscopy, of those representing both gastroenterology and the Spongiform Encephalopathy Advisory Committee are presented in an attempt to guide clinicians as to "best practice" given the current state of our knowledge.

  8. Detection of infectivity in blood of persons with variant and sporadic Creutzfeldt-Jakob disease.

    PubMed

    Douet, Jean Yves; Zafar, Saima; Perret-Liaudet, Armand; Lacroux, Caroline; Lugan, Séverine; Aron, Naima; Cassard, Herve; Ponto, Claudia; Corbière, Fabien; Torres, Juan Maria; Zerr, Inga; Andreoletti, Olivier

    2014-01-01

    We report the presence of infectivity in erythrocytes, leukocytes, and plasma of 1 person with variant Creutzfeldt-Jakob disease and in the plasma of 2 in 4 persons whose tests were positive for sporadic Creutzfeldt-Jakob disease. The measured infectivity levels were comparable to those reported in various animals with transmissible spongiform encephalopathies.

  9. CJD: Understanding Creutzfeldt-Jakob disease.

    PubMed

    Vacca, Vincent M

    2016-03-01

    Rare, transmissible, and rapidly progressive, Creutzfeldt-Jakob disease (CJD) is an ultimately fatal central nervous system infection caused by accumulation of abnormally shaped prion proteins in neurons (see Understanding prion proteins). Although categorized as an infection, CJD doesn't lead to the immune system or inflammatory response typical of most infectious diseases. This article discusses the pathophysiology and diagnosis of this terminal illness and nursing care for patients with suspected or confirmed CJD.

  10. Precautions for Creutzfeldt-Jakob disease.

    PubMed

    Jarvis, W R

    1982-01-01

    Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, fatal disease of the central nervous system. Premortem diagnosis may or may not be conclusive. Because the etiologic agent is virulent, definition of necessary precautions for medical staff associated with such patients is needed. Transmission of CJD in animals has been found to occur after inoculation with brain, spinal cord, liver, kidney, lung, and lymph node tissues in diminishing frequency. Effective methods of sterilization and disinfection for the etiologic agent are unknown. Thus, personnel associated with supposed-CJD patients should take precautions not unlike needle precautions for hepatitis B patients. A list of guidelines is given.

  11. Revised precautionary measures to reduce the possible transmission of Creutzfeldt-Jakob disease (CJD) by blood and blood products; guidance document; availability--FDA. Notice.

    PubMed

    1997-09-23

    The Food and Drug Administration (FDA) is announcing the availability of a guidance document entitled "Revised Precautionary Measures to Reduce the Possible Transmission of Creutzfeldt-Jakob Disease (CJD) by Blood and Blood Products," dated December 11, 1996. The guidance document is intended to provide recommendations to the blood industry and may include information useful to other interested persons.

  12. Familial Creutzfeldt-Jakob disease.

    PubMed

    Haltia, M; Kovanen, J; Van Crevel, H; Bots, G T; Stefanko, S

    1979-08-01

    A Finnish family is described with 9 cases of presenile dementia in 3 generations. The mean age at onset was 52 years (range 46--62 years). Progressive dementia, upper motor neuron signs, muscular rigidity, and twitching, irregular tremors were consistent features in the 6 clinically investigated patients and were associated with spongiform change in the cerebral cortex of one autopsy and two brain biopsy cases. The EEG showed progressive slowing without the occurrence of repetitive high-voltage complexes at any stage of the disease. The average duration of the disease (21 months, range 11--36 months) was longer than in the sporadic form of CJD. The occurrence of CJD within this family follows a pattern consistent with an autosomal dominant mode of inheritance, suggesting the possibility of vertical transmission of the presumptive causative agent for example by genomic integration or transplacental passage. However, the occurrence of the disease only through the paternal line of relationships and the presence of a discordant twin pair argue strongly against transplacental passage or transmission via mother's milk. Simple contact infection also seems unlikely, as conjugal cases were not found among the 7 married patients. The interval between the death of the last affected member in generation IV and the time of onset of the disease in the first affected member of generation V was 10 years. Thus setting a minimum incubation period if case-to-case transmission were occurring. To evaluate the role of a genetically determined susceptibility to infection studies on the HLA antigens and other genetic markers are in progress.

  13. Sleep Pathology in Creutzfeldt-Jakob Disease

    PubMed Central

    Kang, Peter; de Bruin, Gabriela S.; Wang, Leo H.; Ward, Beth A.; Ances, Beau M.; Lim, Miranda M.; Bucelli, Robert C.

    2016-01-01

    Study Objectives: Associations between sleep and neurodegenerative diseases have become increasingly evident. This study aims to characterize the prevalence and type of sleep pathology in Creutzfeldt-Jakob disease (CJD), a rapidly progressive, fatal neurodegenerative disease. Methods: In this observational cross-sectional cohort study, we performed a retrospective analysis of sleep signs and symptoms in a consecutive group of patients with definite CJD at a tertiary care medical center (n = 28). Polysomnography was performed in 14 patients. Results: Although only 5 of 28 patients carried a premorbid sleep diagnosis, signs/symptoms of sleep pathology were present in 25 patients. Eleven reported hypersomnia whereas 13 reported insomnia. Seven had restless legs symptoms and/or periodic limb movements of sleep, and nine reported parasomnias. Of the 14 patients who underwent polysomnography, 1 did not show sleep, 9 (69%) had poorly formed or absent sleep spindles and/or K-complexes, and 10 (77%) had sleep-disordered breathing. Of the 8 patients who experienced rapid eye movement (REM) sleep during the polysomnography, 3 (38%) showed REM sleep without atonia, and 2 patients met criteria for REM sleep behavior disorder. Median total sleep time was 226 (interquartile range [IQR] = 195–282) min. Median sleep efficiency was 58.5% (IQR = 41–65.5 %). Median REM time was 0.35% (IQR = 0–7.125%). Five patients (38%) demonstrated periodic limb movements during polysomnography. One case is presented. Conclusions: Sleep pathology is common in CJD, and screening for sleep pathology is indicated in the evaluation of patients with rapidly progressive dementias. Early identification and treatment of sleep pathology may provide an intervenable target for CJD. Citation: Kang P, de Bruin GS, Wang LH, Ward BA, Ances BM, Lim MM, Bucelli RC. Sleep pathology in Creutzfeldt-Jakob disease. J Clin Sleep Med 2016;12(7):1033–1039. PMID:27250807

  14. Ocular Dipping in Creutzfeldt-Jakob Disease

    PubMed Central

    Llamas, Sara; Gonzalo, Juan Francisco; Sánchez Sánchez, Carmen

    2014-01-01

    Background Ocular dipping (OD), or inverse ocular bobbing, consists of slow, spontaneous downward eye movements with rapid return to the primary position. It has been mainly reported following hypoxic-ischemic encephalopathy, but has also been described in association with other types of diffuse or multifocal encephalopathies and structural brainstem damage. Case Report We report the case of a previously asymptomatic 66-year-old woman who presented with confusion, recent memory disturbances, and abnormal involuntary movements, followed by a coma. Abnormal spontaneous vertical eye movements consistent with OD developed from the fourth day after admission, and the patient died 20 days later. The pathological examination of the brain confirmed the diagnosis of Creutzfeldt-Jakob disease. Conclusions The precise location of damage causing OD is unknown. In contrast to ocular bobbing, OD has no localizing value itself, but structural brainstem damage is likely when it appears combined with other spontaneous vertical eye movements. PMID:24829603

  15. Wernicke encephalopathy and Creutzfeldt-Jakob disease.

    PubMed

    Bertrand, A; Brandel, J P; Grignon, Y; Sazdovitch, V; Seilhean, D; Faucheux, B; Privat, N; Brault, J L; Vital, A; Uro-Coste, E; Pluot, M; Chapon, F; Maurage, C A; Letournel, F; Vespignani, H; Place, G; Degos, C F; Peoc'h, K; Haïk, S; Hauw, J J

    2009-06-01

    We assessed the prevalence of Wernicke encephalopathy (WE) in all 657 cases suspected of Creutzfeldt-Jakob (CJD) referred from 2001 to 2006 to the French Neuropathology Network of CJD. Clinical, biological and imaging data were reviewed when the diagnosis of WE was made at autopsy. No CJD was found in five cases suspected of sporadic CJD. In these five cases, myoclonus had been observed in four, CSF 14-3-3 protein in two. In 14 other cases, WE was combined with CJD, 13 of which were sporadic. These belonged mainly to the molecular variants of sporadic CJD associated with a long duration of disease. This stresses the necessity of remaining alert to the diagnosis of WE when CJD is suspected.

  16. The contribution of different prion protein types and host polymorphisms to clinicopathological variations in Creutzfeldt-Jakob disease.

    PubMed

    Head, Mark W; Ironside, James W

    2012-07-01

    Creutzfeldt-Jakob disease is a fatal neurodegenerative disease that primarily affects the central nervous system. In this respect, it can be considered alongside the more frequently occurring neurodegenerative diseases, such as Alzheimer's disease. Creutzfeldt-Jakob disease is perhaps the paradigmatic protein misfolding disorder, so comparisons between the mechanisms involved in Creutzfeldt-Jakob disease and other neurodegenerative diseases associated with protein misfolding (such as the tauopathies and synucleinopathies) may also be informative. Like many of these diseases, Creutzfeldt-Jakob disease occurs sporadically or can, more rarely, be associated with mutations. However, Creutzfeldt-Jakob disease can also be acquired and is experimentally transmissible. These properties have had profound public health implications and made the disease of interest to virologists, in addition to those interested in protein misfolding disorders and neurodegeneration. The possible causes for the pronounced phenotypic variation among different forms of Creutzfeldt-Jakob disease are beginning to become understood, and these appear to depend in large measure on the genetics of the host (specifically the sequence of the prion protein gene, PRNP) and the epigenetic aspects of the agent (thought to be a misfolded and aggregated form of the PRNP gene product, termed a prion). This review will examine whether this model in its present form has sufficient complexity and subtlety to account for the clinicopathological variation evident in Creutzfeldt-Jakob disease and will outline the ways in which a more complete and informative molecular definition of human prions are currently being sought.

  17. Clinical experiences with Creutzfeldt-Jakob disease: three case studies.

    PubMed

    Szucs, Anna; Várallyay, Péter; Osztie, Eva; Papp, Erzsébet; Sólyom, András; Finta, Lehel; Varga, Dániel; Barcs, Gábor; Holló, András; Kamondi, Anita

    2012-11-30

    The clinical picture, electroencephalographic, imaging and cerebrospinal fluid parameters as well as the molecular background of Creutzfeldt-Jakob disease have been well explored. The diagnostic criteria, offering clinicians a fair chance to identify these patients in vivo, have recently been updated. However, the diagnosis is still a challenge in everyday neurological routine. We report on three of our Creutzfeldt-Jakob patients for calling attention to the classical and the recently defined features of the disease. We conclude that based on the rapidly progressing neuropsychiatric syndrome Creutzfeldt-Jakob disease may be suspected; follow-up EEG may reveal the typical (pseudo)-periodic pattern with progressive deterioration of the background activity. In addition, diffusion-weighted brain MRI imaging (DWI) has high diagnostic value. Detection of 14-3-3 protein in the cerebrospinal fluid supports the in vivo diagnosis.

  18. Rapid cognitive decline: not always Creutzfeldt-Jakob disease.

    PubMed

    Randall, A; Ellis, R; Hywel, B; Davies, R R; Alusi, S H; Larner, A J

    2015-01-01

    A patient with rapidly progressive cognitive decline over an approximately four month period was suspected to have sporadic Creutzfeldt-Jakob disease. Features thought to support this diagnosis included psychiatric symptoms (anxiety and depression), visual hallucinations and a visual field defect. However, the finding of papilloedema broadened the differential diagnosis. Although standard brain imaging and electroencephalography had shown only non-specific abnormalities, subsequent cerebral angiography disclosed an intracranial dural arteriovenous fistula. Following embolisation, the patient made a good functional recovery. Intracranial dural arteriovenous fistula merits consideration in any patient with subacute cognitive decline, and should be included in the differential diagnosis of sporadic Creutzfeldt-Jakob disease.

  19. White matter involvement in sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Mandelli, Maria Luisa; DeArmond, Stephen J.; Hess, Christopher P.; Vitali, Paolo; Papinutto, Nico; Oehler, Abby; Miller, Bruce L.; Lobach, Irina V.; Bastianello, Stefano; Geschwind, Michael D.; Henry, Roland G.

    2014-01-01

    Sporadic Creutzfeldt-Jakob disease is considered primarily a disease of grey matter, although the extent of white matter involvement has not been well described. We used diffusion tensor imaging to study the white matter in sporadic Creutzfeldt-Jakob disease compared to healthy control subjects and to correlated magnetic resonance imaging findings with histopathology. Twenty-six patients with sporadic Creutzfeldt-Jakob disease and nine age- and gender-matched healthy control subjects underwent volumetric T1-weighted and diffusion tensor imaging. Six patients had post-mortem brain analysis available for assessment of neuropathological findings associated with prion disease. Parcellation of the subcortical white matter was performed on 3D T1-weighted volumes using Freesurfer. Diffusion tensor imaging maps were calculated and transformed to the 3D-T1 space; the average value for each diffusion metric was calculated in the total white matter and in regional volumes of interest. Tract-based spatial statistics analysis was also performed to investigate the deeper white matter tracts. There was a significant reduction of mean (P = 0.002), axial (P = 0.0003) and radial (P = 0.0134) diffusivities in the total white matter in sporadic Creutzfeldt-Jakob disease. Mean diffusivity was significantly lower in most white matter volumes of interest (P < 0.05, corrected for multiple comparisons), with a generally symmetric pattern of involvement in sporadic Creutzfeldt-Jakob disease. Mean diffusivity reduction reflected concomitant decrease of both axial and radial diffusivity, without appreciable changes in white matter anisotropy. Tract-based spatial statistics analysis showed significant reductions of mean diffusivity within the white matter of patients with sporadic Creutzfeldt-Jakob disease, mainly in the left hemisphere, with a strong trend (P = 0.06) towards reduced mean diffusivity in most of the white matter bilaterally. In contrast, by visual assessment there was no white

  20. White matter involvement in sporadic Creutzfeldt-Jakob disease.

    PubMed

    Caverzasi, Eduardo; Mandelli, Maria Luisa; DeArmond, Stephen J; Hess, Christopher P; Vitali, Paolo; Papinutto, Nico; Oehler, Abby; Miller, Bruce L; Lobach, Irina V; Bastianello, Stefano; Geschwind, Michael D; Henry, Roland G

    2014-12-01

    Sporadic Creutzfeldt-Jakob disease is considered primarily a disease of grey matter, although the extent of white matter involvement has not been well described. We used diffusion tensor imaging to study the white matter in sporadic Creutzfeldt-Jakob disease compared to healthy control subjects and to correlated magnetic resonance imaging findings with histopathology. Twenty-six patients with sporadic Creutzfeldt-Jakob disease and nine age- and gender-matched healthy control subjects underwent volumetric T1-weighted and diffusion tensor imaging. Six patients had post-mortem brain analysis available for assessment of neuropathological findings associated with prion disease. Parcellation of the subcortical white matter was performed on 3D T1-weighted volumes using Freesurfer. Diffusion tensor imaging maps were calculated and transformed to the 3D-T1 space; the average value for each diffusion metric was calculated in the total white matter and in regional volumes of interest. Tract-based spatial statistics analysis was also performed to investigate the deeper white matter tracts. There was a significant reduction of mean (P=0.002), axial (P=0.0003) and radial (P=0.0134) diffusivities in the total white matter in sporadic Creutzfeldt-Jakob disease. Mean diffusivity was significantly lower in most white matter volumes of interest (P<0.05, corrected for multiple comparisons), with a generally symmetric pattern of involvement in sporadic Creutzfeldt-Jakob disease. Mean diffusivity reduction reflected concomitant decrease of both axial and radial diffusivity, without appreciable changes in white matter anisotropy. Tract-based spatial statistics analysis showed significant reductions of mean diffusivity within the white matter of patients with sporadic Creutzfeldt-Jakob disease, mainly in the left hemisphere, with a strong trend (P=0.06) towards reduced mean diffusivity in most of the white matter bilaterally. In contrast, by visual assessment there was no white matter

  1. Bitemporal hypometabolism in Creutzfeldt-Jakob disease measured by positron emission tomography with (/sup 18/F)-2-fluorodeoxyglucose

    SciTech Connect

    Friedland, R.P.; Prusiner, S.B.; Jagust, W.J.; Budinger, T.F.; Davis, R.L.

    1984-10-01

    It is well established that Creutzfeldt-Jakob disease (CJD) is caused by a slow infectious agent similar to the scrapie prion. However, the pathogenesis of this infection is poorly understood. Positron emission tomography (PET) was performed on a 54-year-old man with autopsy confirmed CJD using (18F)-2-fluorodeoxyglucose (FDG) and the Donner 280-crystal tomograph. Temporal lobe hypometabolism with hemispheric asymmetry was observed. These findings are similar to those previously obtained in PET-FDG studies of patients with clinically defined Alzheimer disease (AD). The similarities in the regional metabolic alterations between CJD and AD provide additional evidence for the possibility that AD may be caused by a slow infectious prion.

  2. Abnormal Eye Movements in Creutzfeldt-Jakob Disease

    NASA Technical Reports Server (NTRS)

    Grant, Michael P.; Cohen, Mark; Petersen, Robert B.; Halmagyi, G. Michael; McDougall, Alan; Tusa, Ronald J.; Leigh, R. John

    1993-01-01

    We report 3 patients with autopsy-proven Creutzfeldt-Jakob disease who, early in their course, developed abnormal eye movements that included periodic alternating nystagmus and slow vertical saccades. These findings suggested involvement of the cerebellar nodulus and uvula, and the brainstem reticular formation, respectively. Cerebellar ataxia was also an early manifestation and, in one patient, a frontal lobe brain biopsy was normal at a time when ocular motor and cerebellar signs were conspicuous. As the disease progressed, all saccades and quick phases of nystagmus were lost, but periodic alternating gaze deviation persisted. At autopsy, 2 of the 3 patients had pronounced involvement of the cerebellum, especially of the midline structures. Creutzfeldt-Jakob disease should be considered in patients with subacute progressive neurological disease when cognitive changes are overshadowed by ocular motor findings or ataxia.

  3. Abnormal Eye Movements in Creutzfeldt-Jakob Disease

    NASA Technical Reports Server (NTRS)

    Grant, Michael P.; Cohen, Mark; Petersen, Robert B.; Halmagyi, G. Michael; McDougall, Alan; Tusa, Ronald J.; Leigh, R. John

    1993-01-01

    We report 3 patients with autopsy-proven Creutzfeldt-Jakob disease who, early in their course, developed abnormal eye movements that included periodic alternating nystagmus and slow vertical saccades. These findings suggested involvement of the cerebellar nodulus and uvula, and the brainstem reticular formation, respectively. Cerebellar ataxia was also an early manifestation and, in one patient, a frontal lobe brain biopsy was normal at a time when ocular motor and cerebellar signs were conspicuous. As the disease progressed, all saccades and quick phases of nystagmus were lost, but periodic alternating gaze deviation persisted. At autopsy, 2 of the 3 patients had pronounced involvement of the cerebellum, especially of the midline structures. Creutzfeldt-Jakob disease should be considered in patients with subacute progressive neurological disease when cognitive changes are overshadowed by ocular motor findings or ataxia.

  4. A Heidenhain variant of Creutzfeldt-Jakob disease: forensic implication.

    PubMed

    Rizzo, M; Bruni, A; Barberio, C; Magro, G; Foncin, J F

    2004-12-02

    To investigate whether typical clinical, diagnostic and neuropathological findings can be identified in a patient with a postmortem diagnosis of a Heidenhain variant of Creutzfeldt-Jakob disease (CJD). We report a new case of CJD in a rare variant. A man admitted to hospital with cefalea and vision disorder. Clinical and neurological examination showed headache, vision reduction, psychomotor anxiety and progressive torpor. The patient died 4 h after admission to hospital. The autopsy findings included marked encephalic vascular congestion. Hystoneurology examination showed no macroscopic anomaly. Microscopy findings included neuronal loss, gliosis in striate area with arachnoid cells and cerebellum microspongiosis. Creutzfeldt-Jakob disease is a rare neurodegenerative human disorder. The prion hypothesis as an explanatory model is currently favoured by majority of researchers. A disease course described by Heidenhain including the leading symptoms of a visual disorder and rapid progression. This report emphasize the multidisciplinary role (forensic, neurogenetic and neurohistologic) for diagnosis and to standardize a protocol to investigate.

  5. Creutzfeldt-Jakob disease: a case report and differential diagnoses.

    PubMed

    Kojima, Gotaro; Tatsuno, Brent K; Inaba, Michiko; Velligas, Stephanie; Masaki, Kamal; Liow, Kore K

    2013-04-01

    Sporadic Creutzfeldt-Jakob disease is a rare neurodegenerative disorder of unknown etiology that causes rapidly progressive dementia. This disease is uniformly fatal and most patients die within 12 months. Clinical findings include myoclonus, visual disturbances, and cerebellar and pyramidal/extrapyramidal signs in addition to rapidly progressive cognitive and functional impairment. These findings are all non-specific and it is often difficult and challenging to diagnose premortem because of low awareness and clinical suspicion. We present a 66-year-old woman with a 5-month history of rapidly progressive dementia. After a series of extensive diagnostic examinations and continuous follow-up, she was diagnosed with probable sporadic Creutzfeldt-Jakob disease based on Centers for Disease Control and Prevention (CDC) criteria, with key findings of rapidly progressive dementia, blurry vision, extrapyramidal signs (cogwheel rigidity), and abnormal hyperintensity signals on diffusion-weighted MRI. Her symptoms progressively worsened and she died 7 months after the onset. The postmortem brain autopsy demonstrated the presence of abnormal protease-resistant prion protein by Western Blot analysis. A literature review was performed on differential diagnoses that present with rapidly progressive dementia and thereby mimic sporadic Creutzfeldt-Jakob disease. These include Alzheimer's disease, dementia with Lewy Bodies, frontotemporal dementia, meningoencephalitis, corticobasal degeneration, progressive supranuclear palsy, CADASIL, and paraneoplastic encephalomyelitis.

  6. Bitemporal hypometabolism in Creutzfeldt-Jakob Disease measured by positron emission tomography with (F-18)2-fluorodeoxyglucose

    SciTech Connect

    Friedland, R.P.; Budinger, T.F.; Prusiner, S.B.; Jagust, W.J.

    1984-01-01

    It is well established that Creutzfeldt-Jakob Disease (CJD) is caused by a slow infectious agent similar to the scrapie prion. However, the pathogenesis of this infection is poorly understood. Positron emission tomography (PET) was performed on a 54 year old male subject with autopsy confirmed CJD using (F-18)2-fluorodeoxyglucose (FDG) and the Donner 280-crystal tomograph. An x-ray computed tomographic study of the brain performed 4 days prior to PET was normal. In the PET study the frontal to temporal cortex difference of activity densities was 30% on the left and 12% on the right, reflecting temporal hypometabolism. The left-right temporal cortex difference of activity density was 25%, documenting marked hemispheric asymmetry. These findings are similar to those previously obtained in PET-FDG studies of patients with clinically defined Alzheimer's Disease (AD) and are distinctly different from PET-FDG finding in patients with other dementing illnesses or in healthy aged subjects. Recent work has demonstrated extensive biological similarities between CJD, scrapie and AD. The similarities in the regional metabolic alterations between CJD and AD provide additional evidence for the hypothesis that AD is caused by a slow infectious (prion-like) pathogen.

  7. Sporadic Creutzfeldt-Jakob disease--a review.

    PubMed

    Sharma, Stuti; Mukherjee, Madhurima; Kedage, Vivekananda; Muttigi, Manjunatha S; Rao, Anjali; Rao, Suryanarayana

    2009-01-01

    The objective is to study a patient with sporadic Creutzfeldt-Jakob disease (CJD). The patient, a 70-year-old woman with a history spanning over 1 month, with acute onset, progressive abnormal behavior, and cognitive decline with generalized asymmetrical myoclonic jerking, startle phenomenon, and cortical blindness, was referred to the hospital. On observation of clinical symptoms, metabolic and hematological investigations, MRI (magnetic resonance imaging), and EEG (electroencephalogram) were done. The clinical symptoms, MRI, and diagnostic EEG were suggestive of sporadic CJD. Other metabolic encephalopathies were ruled out. With sodium valproate and clonezepam, her myoclonic jerks improved slightly. As CJD is an incurable disease, no definitive treatment could be given.

  8. Physical properties of the Creutzfeldt-Jakob disease agent

    SciTech Connect

    Sklaviadis, T.K.; Manuelidis, L.; Manuelidis, E.E.

    1989-03-01

    In this report, the authors present the first physical characterization of the Creutzfeld-Jakob disease agent. Preparations with high yields of infectivity (assayed infectious units) were obtained by a novel, gentle procedure in which initially sedimenting Gp34 (prion protein) was disaggregated by a variety of criteria with no subsequent loss of infectivity. Studies with this preparation indicate that most of the Creutzfeldt-Jakob disease agent has both a viruslike size and density. In velocity sedimentation and isopycnic sucrose gradients, infectivity comigrated with nucleic acid-protein complexes of appreciable size.

  9. Steroid-responsive Hashimoto encephalopathy mimicking Creutzfeldt-Jakob disease.

    PubMed

    Santoro, Domenico; Colombo, Irene; Ghione, Isabella; Peverelli, Lorenzo; Bresolin, Nereo; Sciacco, Monica; Prelle, Alessandro

    2011-08-01

    Hashimoto's encephalopathy (HE) is a rare neurological disorder with a heterogeneous group of neurological symptoms associated with high titres of anti-thyroid antibodies. Clinical manifestations may include encephalopathic features such as seizures, behavioural and psychiatric manifestations, movement disorders and coma. The objective of this presentation is to describe a patient with this rare and controversial clinical syndrome mimicking Creutzfeldt-Jakob disease, associated with a Hashimoto euthyroid thyroiditis and with a significant response to high dose intravenous prednisone. The responsiveness of this syndrome to steroids suggests that this disorder involves immune pathogenic mechanisms, as previous reviews reported.

  10. Preliminary risk analysis applied to the transmission of Creutzfeldt-Jakob disease.

    PubMed

    Bertrand, E; Schlatter, J

    2011-01-01

    Transmissible spongiform encephalopathy (TSE) is a degenerative disease of the central nervous system. As yet, there is no human screening test and no effective treatment. This disease is invariably fatal. General preventive measures are therefore essential. The objective of this study is to analyze and address on a prioritized basis the risks relating to the transmission of Creutzfeldt-Jakob disease during surgical operations by means of a preliminary risk analysis (PRA). The PRA produces 63 scenarios with maximum risk relating to operational and legal dangers. The study recommends a number of courses of action, such as training and internal controls, in order to reduce the risks identified. A procedure has been drawn up and assessed for each action. This PRA makes it possible to target and significantly reduce the potential dangers for transmission of Creutzfeldt-Jakob disease through the use of medical instruments.

  11. [Creutzfeldt-Jakob disease in Peru: report of eleven cases].

    PubMed

    Torres-Ramírez, Luis; Ramírez-Quiñones, Jorge; Cosentino-Esquerre, Carlos; Vélez-Rojas, Miriam; Flores-Mendoza, Martha; Rivas-Franchini, Diana; Suarez-Reyes, Rafael; Núñez-Coronado, Yesenia

    2014-04-01

    Creutzfeldt-Jakob disease (CJD) is a fatal neurological disease caused by pathological isoform of the human prion protein. Clinical features of six cases of the sporadic form of CJD with definitive diagnosis by histopathology, and five cases with probable diagnosis were reported in patients treated at the Peruvian National Institute of Neurological Sciences. The average age of onset in definite cases was 55.8 years and in probable cases was 59.6, mostly males. The average disease duration was 8.8 months. A typical EEG was found in 50% of definite cases and in 80% of probable. The 14-3-3 protein in cerebrospinal fluid was positive in a probable case, and typical MRI findings were observed in two probable cases. All cases studied had a typical clinical course of the disease, and it is considered as the first report of CJD in Peru.

  12. Creutzfeldt-Jakob disease surveillance in Australia, update to December 2013.

    PubMed

    Klug, Genevieve M; Boyd, Alison; Sarros, Shannon; Stehmann, Christiane; Simpson, Marion; McLean, Catriona A; Masters, Collin L; Collins, Stephen J

    2014-12-31

    Nation-wide surveillance of transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease, is performed by the Australian National Creutzfeldt-Jakob Disease Registry, based at the University of Melbourne. Surveillance has been undertaken since 1993. Over this dynamic period in transmissible spongiform encephalopathy research and understanding, the unit has evolved and adapted to changes in surveillance practices and requirements, the emergence of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness and understanding of Creutzfeldt-Jakob disease and other transmissible spongiform encephalopathies in the health care setting. In 2013, routine surveillance continued and this brief report provides an update of the surveillance data collected by the Australian National Creutzfeldt-Jakob Disease Registry prospectively from 1993 to December 2013, and retrospectively to 1970. The report highlights the recent multi-national collaborative study published that has verified the correlation between surveillance intensity and reported disease incidence.

  13. Creutzfeldt-Jakob disease: report of four cases and review of the literature.

    PubMed

    Atalay, Fatma Öz; Tolunay, Şahsine; Özgün, Gonca; Bekar, Ahmet; Zarifoğlu, Mehmet

    2015-01-01

    Creutzfeldt-Jakob disease is a very rare, progressive neurodegenerative disorder that is incurable and always fatal. It is one of the transmissible spongiform encephalopathies caused by prions. Multiple vacuoles in neuropil and neuronal loss in the gray matter gives the classical sponge-like appearance of brain and are responsible for the typical clinical symptoms. In this report, we present 4 cases referred to the neurology department of Uludağ University with neurological symptoms. Patients were evaluated with electroencephalogram and magnetic resonance imaging, and performed brain biopsies for further investigation. For definitive diagnosis of Creutzfeldt-Jakob disease, accumulation of prion protein in brain was detected immunohistochemically. Patients died within weeks in consequence of rapid progression of the disease. Although Creutzfeldt-Jakob disease is an infrequent disorder, when a patient presents with characteristic clinical symptoms such as rapidly progressive dementia with myoclonus, the diagnosis of Creutzfeldt-Jakob disease should be taken into consideration.

  14. Visual art therapy in sporadic Creutzfeldt-Jakob disease: a case study.

    PubMed

    Shrestha, Rajeet; Trauger-Querry, Barbara; Loughrin, Athena; Appleby, Brian S

    2016-01-01

    This paper describes the diagnostic and treatment utility of visual art therapy in a case of sporadic Creutzfeldt-Jakob disease. Visual art therapy was compared longitudinally with clinical and neuroimaging data over five-month period in an autopsy-confirmed case of sporadic Creutzfeldt-Jakob disease of MM2-cortical subtype. Art therapy sessions and content were useful in ascertaining neuropsychiatric symptoms during the course of her illness. Art therapy offered a unique emotional and cognitive outlet as illness progressed. Patients and families affected by sporadic Creutzfeldt-Jakob disease may benefit from art therapy despite the rapidly progressive nature of the illness. Art therapy can also be useful for assessment of patients with sporadic Creutzfeldt-Jakob disease by healthcare professionals.

  15. Severe hypoxia and multiple infarctions resembling Creutzfeldt-Jakob disease.

    PubMed

    Mittelbronn, Michel; Capper, David; Bader, Benedikt; Schittenhelm, Jens; Haybaeck, Johannes; Weber, Petra; Meyermann, Richard; Kretzschmar, Hans A; Wietholter, Horst

    2008-01-01

    Although neuropathological examination is still required for the definite diagnosis of Creutzfeldt-Jakob disease (CJD), specialised clinical assessment predicts probable CJD. Here we present a 73-year-old female patient presenting with rapid cognitive decline, visual, acoustic and cerebellar disturbances, ataxia and EEG changes compatible with early CJD stages. MRI revealed hyperintensities within the thalami, hypothalami, corpora mammillaria, the tectum and the cortex. Initial neuropathological examination showed severe cortical and subcortical spongiosis. However, both immunohistochemistry and Western blotting showed no pathological prion protein. Finally, small infarctions affecting the tectum, tegmentum, corpora mammillaria and global hypoxic-ischaemic changes could be identified as the probable reason for the changes interpreted as CJD-related pathology. Hypoxic-ischaemic CNS alterations mainly affecting the supply area of the basilar artery should be ruled out in case of probable CJD. In addition, severe spongiosis can be misleading in the histological examination, suggesting the diagnosis of a prion-induced spongiform encephalopathy.

  16. A case of pure autotopagnosia following Creutzfeldt-Jakob disease.

    PubMed

    Tamura, Itaru; Hamada, Shinsuke; Soma, Hiroyuki; Moriwaka, Fumio; Tashiro, Kunio

    2016-12-02

    A 69-year-old male (N.A.) with Creutzfeldt-Jakob disease showed pure autotopagnosia. We administered tests evaluating his ability to name his own body parts, to point to body parts (his own and examiner's), and to recognize positional relationships between his body parts by verbal questions and responses. We found impaired localization of the patient's own body parts by pointing and impaired recognition of positional relationships between his body parts. However, there was no impairment in naming his own body parts or in localizing the examiner's body parts. The results suggest a pure autotopagnosia in N.A. leading to an impairment of recognition of the spatial position of his body parts in a three-dimensional body representation within the egocentric reference frame. We were able to rule out the possibility that his pattern of performance could have been due to a disability in programming reaching movements of the arm.

  17. Classification of sporadic Creutzfeldt-Jakob disease revisited.

    PubMed

    Cali, Ignazio; Castellani, Rudolph; Yuan, Jue; Al-Shekhlee, Amer; Cohen, Mark L; Xiao, Xiangzhu; Moleres, Francisco J; Parchi, Piero; Zou, Wen-Quan; Gambetti, Pierluigi

    2006-09-01

    The sporadic form of Creutzfeldt-Jakob disease (sCJD) has been classified on the basis of the molecular mass of the protease-resistant scrapie prion protein (PrP(Sc)), which can be type 1 or type 2, and the genotype at the methionine (M)/valine (V) polymorphic codon 129, which can be MM, MV or VV. In one classification proposed by Parchi et al., [Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, Zerr I , Budka H , Kopp N , Piccardo P , Poser S , Rojiani A , Streichemberger N , Julien J , Vital C , Ghetti B , Gambetti P , Kretzschmar H . Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46: 224-33.] the most common subtype of sCJD, designated sCJDMM1, is viewed as a single entity. Two other classifications proposed by Collinge et al. [Collinge J, Sidle KC, Meads J, Ironside J, Hill AF. Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD. Nature 1996; 383: 685-90.] and Zanusso et al., [Zanusso G, Farinazzo A, Fiorini M, Gelati M, Castagna A, Righetti PG, Rizzuto N, Monaco S . pH-dependent prion protein conformation in classical Creutzfeldt-Jakob disease. J Biol Chem 2001; 276: 40377-80.] respectively, subdivide sCJDMM1 into two subtypes on the basis of the different molecular mass and phenotypic characteristics, primarily disease duration. To resolve this discrepancy, we divided a group of 22 subjects with confirmed sCJDMM1 according to Parchi et al. into two sub-populations according to whether the disease duration was <5 months (short-duration subjects) or >7 months (long-duration subjects). We then examined the PrP(Sc) molecular mass under the conditions that allowed wide variability of the pH of the PrP(Sc) preparations as well as under stringent pH conditions, using high-resolution gel electrophoresis. We also compared the characteristics of the PrP(Sc) associated with the short- and long-duration subjects using two

  18. Review: Laboratory diagnosis and surveillance of Creutzfeldt-Jakob disease.

    PubMed

    Lee, Jeongmin; Hyeon, Jae Wook; Kim, Su Yeon; Hwang, Kyu-Jam; Ju, Young Ran; Ryou, Chongsuk

    2015-01-01

    Creutzfeldt-Jakob disease (CJD) is a representative human transmissible spongiform encephalopathy associated with central nervous system degeneration. Prions, the causative agents of CJD, are composed of misfolded prion proteins and are able to self-replicate. While CJD is a rare disease affecting only 1-1.5 people per million worldwide annually, it has attracted both scientific and public attention as a threatening disease since an epidemic of variant CJD (vCJD) cases appeared in the mid-1990s. Due to its unconventional transmission and invariable fatality, CJD poses a serious risk to public health. The hundreds of sporadic, genetic, and iatrogenic CJD cases as well as potential zoonotic transmission suggest that CJD is an ongoing concern for the field of medicine. Nevertheless, treatment aimed at clinical prevention and treatment that reverses the course of disease does not exist currently. Active surveillance and effective laboratory diagnosis of CJD are, therefore, critical. In this report, the surveillance systems and laboratory tests used currently to diagnose CJD in different countries are reviewed. The current efforts to improve surveillance and diagnosis for CJD using molecular and biochemical findings are also described.

  19. "Preclinical" MSA in definite Creutzfeldt-Jakob disease.

    PubMed

    Rodriguez-Diehl, Roberta; Rey, Maria Jesus; Gironell, Alexandre; Martinez-Saez, Elena; Ferrer, Isidre; Sánchez-Valle, Raquel; Jagüe, Jordi; Nos, Carlos; Gelpi, Ellen

    2012-04-01

    Multiple system atrophy (MSA) is a sporadic alpha-synucleinopathy clinically characterized by variable degrees of parkinsonism, cerebellar ataxia and autonomic dysfunction. The histopathological hallmark of MSA is glial cytoplasmic inclusion (GCI). It is considered to represent the earliest stage of the degenerative process in MSA and to precede neuronal degeneration. Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal, rapidly progressive dementia generally associated with ataxia, pyramidal and extrapyramidal symptoms and myoclonus. Definite diagnosis needs neuropathological demonstration of variable degrees of spongiform degeneration of neuropil, neuronal loss, astro- and microgliosis, and the presence of abnormal deposits of the misfolded prion protein PrP(res) . Both diseases, CJD and MSA are infrequent among neurodegenerative diseases. In the present report we describe clinical and neuropathological findings of a previously healthy 64-year-old woman who developed symptoms of classical CJD. At post mortem examination, the brain showed in addition to classical methionine/methionine PrP(res) type 1 (MM1) sCJD changes and moderate Alzheimer-type pathology, features of "preclinical" MSA with minimal histopathological changes. These were characterized by discrete amounts of alpha-synuclein immunoreacive glial cytoplasmic inclusions in the striato-nigral system, isolated intraneuronal inclusions in pigmented neurons of the substantia nigra, as well as some vermiform intranuclear inclusions. To our knowledge, this is the first report on the coexistence of definite sCJD and "minimal changes" MSA in the same patient.

  20. Visual symptoms in the presentation of Creutzfeldt-Jakob disease.

    PubMed

    Wong, Aaron; Matheos, Kaliopy; Danesh-Meyer, Helen V

    2015-10-01

    We describe a 68-year-old man with a previous history of neurosurgical repair of a skull fracture, who presented to the ophthalmology clinic with progressive visual decline. His initial visual acuity was 6/30 in the right eye and 6/48 in the left, and over 2 weeks this progressed to hand movements in both eyes. No ocular abnormalities were identified. He was noted to be increasingly confused and a subsequent MRI showed extensive bilateral posterior cortical changes consistent with cytotoxic oedema. An electroencephalogram was suggestive of encephalopathy, particularly involving the occipital lobe. He was diagnosed with the Heidenhain variant of Creutzfeldt-Jakob disease (CJD), confirmed by a positive cerebrospinal fluid 14-3-3 protein. Classically, patients with CJD present with rapidly progressive cognitive decline, ataxia and myoclonus. However, visual symptoms are a common and perhaps underrecognised manifestation of CJD. Patients can present with isolated visual symptoms which precede cognitive decline by weeks due to predominantly occipital lobe disease. This presentation is classified as the Heidenhain variant of CJD.

  1. [Creutzfeldt-Jakob disease in the squirrel monkeys].

    PubMed

    Cathala, F; Court, L; Breton, P; Mestries, J C; Gourmelon, P; Dormont, D; Lemercier, M; Gray, F; Hauw, J J; Escourolle, R; Gibbs, C J; Gajdusek, C D

    1981-01-01

    Four different strains of Creutzfeldt-Jakob disease virus (2 primary and 2 passaged in primates or mice) were inoculated intra-cerebrally into squirrel monkeys implanted with continuously-recording indwelling electrodes. Simultaneous EEC and videotape recordings were made on unrestrained animals. In addition EEG recordings were made of evoked visual potentials on restrained animals. EEG abnormalities appeared in every animal before the first clinical signs (6 to 20 months after inoculation) and included generalized slowing, epileptiform patterns and occasional episodes of pseudo-periodic activity. Abnormal evoked visual potentials and disturbances of consciousness were also noted. All viral strains produced similar disorders and the death of inoculated animals. The relative frequency of epilepsy seen in the CJD-inoculated squirrel monkey contrasts with its irregular occurrence in most other monkey species, and its total absence in the spider monkey. This could be related to the lesser complexity of neo-cortical evolution in the squirrel monkey and a less pronounced development of inhibitory CNS mechanisms under the general control of GABA-ergic neurons.

  2. Nestin immunoreactivity of Purkinje cells in Creutzfeldt-Jakob disease.

    PubMed

    Mizuno, Yuji; Ohama, Eisaku; Hirato, Junko; Nakazato, Yoichi; Takahashi, Hitoshi; Takatama, Masamitsu; Takeuchi, Toshiyuki; Okamoto, Koichi

    2006-07-15

    Nestin, an intermediate filament protein, is mainly expressed in neural progenitor/stem cells in the central nervous system. Recently, we reported that nestin is expressed in Purkinje cells in patients with Creutzfeldt-Jakob disease (CJD). In this study, we examined a total of 19 CJD cerebella to analyze the intensity and pattern of nestin immunoreactivity of Purkinje cells in different pathological stages of degeneration in the cerebellar cortex. The results showed that the Purkinje cells were immunoreactive with nestin regardless of the severity of degenerative cerebellar cortex. Furthermore, we noted several different types of nestin immunoreactivity, indicated by diffuse and fine, coarse, and inclusion-like immunostainings within Purkinje cell bodies as well as dot-like staining outside of the cell bodies. In contrast, on examination of cerebella from non-CJD patients, 6 of 30 cases showed nestin immunoreactivity to a lesser extent. Thus, nestin-positive Purkinje cells are more common in CJD cerebella than in non-CJD cerebella. Although the mechanism of nestin expression in Purkinje cells is not yet understood, we suggest that such nestin-positive Purkinje cells are being reactivated to survive the cell death.

  3. Creutzfeldt-Jakob disease surveillance in Australia: update to December 2015.

    PubMed

    Klug, Genevieve M; Boyd, Alison; Sarros, Shannon; Stehmann, Christiane; Simpson, Marion; McLean, Catriona A; Masters, Colin L; Collins, Steven J

    2016-09-30

    Nation-wide surveillance of human transmissible spongiform encephalopathies (also known as prion diseases), the most common being Creutzfeldt-Jakob disease, is performed by the Australian National Creutzfeldt-Jakob Disease Registry, based at the University of Melbourne. Prospective surveillance has been undertaken since 1993 and over this dynamic period in transmissible spongiform encephalopathy research and understanding, the unit has evolved and adapted to changes in surveillance practices and requirements concomitant with the delineation of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness of prion diseases in the health care setting. In 2015, routine national surveillance continued and this brief report provides an update of the cumulative surveillance data collected by the Australian National Creutzfeldt-Jakob Disease Registry prospectively from 1993 to December 2015, and retrospectively to 1970.

  4. Creutzfeldt-Jakob disease surveillance in Australia: update to December 2014.

    PubMed

    Klug, Genevieve M; Boyd, Alison; Sarros, Shannon; Stehmann, Christiane; Simpson, Marion; McLean, Catriona; Masters, Colin L; Collins, Steven J

    2016-06-30

    Nation-wide surveillance of human transmissible spongiform encephalopathies (also known as prion diseases), the most common being Creutzfeldt-Jakob disease, is performed by the Australian National Creutzfeldt-Jakob Disease Registry, based at the University of Melbourne. Prospective surveillance has been undertaken since 1993 and over this dynamic period in transmissible spongiform encephalopathy research and understanding, the unit has evolved and adapted to changes in surveillance practices and requirements concomitant with the emergence of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness of prion diseases in the health care setting. In 2014, routine national surveillance continued and this brief report provides an update of the cumulative surveillance data collected by the Australian National Creutzfeldt-Jakob Disease Registry prospectively from 1993 to December 2014, and retrospectively to 1970.

  5. Iatrogenic Creutzfeldt-Jakob disease via surgical instruments.

    PubMed

    Thomas, Jonathan G; Chenoweth, Carol E; Sullivan, Stephen E

    2013-09-01

    Creutzfeldt-Jakob disease (CJD) is a neurodegenerative prion disease that can spread via contaminated neurosurgical instruments previously used on an infected patient. We examine current guidelines on how to recognize, handle, and prevent instrument-related iatrogenic CJD. Despite only four reported patients worldwide implicating contaminated neurosurgical instruments, and none in the past 30 years, the public health consequences of potential instrument-related iatrogenic CJD can be far-reaching. Conventional sterilization and disinfection methods are inadequate in reducing prion infectivity of contaminated instruments, and World Health Organization recommendations for disinfection using bleach or sodium hydroxide are often impractical for routine decontamination. Recently, possible CJD exposure via infected surgical instruments was suspected at a large teaching hospital. Although CJD was later disproven, the intervening investigation exposed the difficulty in tracking infected surgical instruments and in protecting subsequent surgical patients from prion infection. To identify patients at risk for iatrogenic CJD, infectivity of instruments after this index patient is estimated using simple scenario modeling, assuming a certain log reduction of infectivity for each cleansing cycle. Scenario modeling predicts that after six cycles of instrument use with conventional cleansing following an index patient, other patients are highly unlikely to be at risk for iatrogenic CJD. Despite its rarity, the threat of iatrogenic CJD transmission via contaminated instruments poses tremendous challenges to neurosurgeons. Basic prevention strategies should be employed for patients with suspected CJD, including use of disposable instruments where possible and quarantining non-disposable instruments until the diagnosis is ascertained, or using special instrument reprocessing methods if CJD is suspected.

  6. Pathologically confirmed autoimmune encephalitis in suspected Creutzfeldt-Jakob disease

    PubMed Central

    Maat, Peter; de Beukelaar, Janet W.; Jansen, Casper; Schuur, Maaike; van Duijn, Cornelia M.; van Coevorden, Marleen H.; de Graaff, Esther; Titulaer, Maarten; Rozemuller, Annemieke J.

    2015-01-01

    Objective: To determine the clinical features and presence in CSF of antineuronal antibodies in patients with pathologically proven autoimmune encephalitis derived from a cohort of patients with suspected Creutzfeldt-Jakob disease (CJD). Methods: The Dutch Surveillance Centre for Prion Diseases performed 384 autopsies on patients with suspected CJD over a 14-year period (1998–2011). Clinical information was collected from treating physicians. Antineuronal antibodies were tested in CSF obtained postmortem by immunohistochemistry on fresh frozen rat brain sections, by Luminex assay for the presence of well-characterized onconeural antibodies, and by cell-based assays for antibodies against NMDAR, GABABR1/2, GABAAR GLUR1/2, LGI1, Caspr2, and DPPX. Results: In 203 patients, a diagnosis of definite CJD was made, while in 181 a variety of other conditions were diagnosed, mainly neurodegenerative. In 22 of these 181, the neuropathologist diagnosed autoimmune encephalitis. One patient was excluded because of lack of clinical information. Inflammatory infiltrates were predominantly perivascular and consisted mainly of T cells. The predominant locations were basal ganglia and thalamus (90%) and temporal lobes and hippocampus (81%). In 6 patients (29%), antineuronal antibodies were detected in postmortem CSF, directed against Hu, NMDAR, GABABR1/2, Caspr2, and an unidentified synaptic antigen in 2. The most frequent symptoms were dementia (90%), gait disturbance (86%), cerebellar signs (67%), and neuropsychiatric symptoms (67%). Immunopathologic and clinical findings did not differ between autoantibody-negative patients and patients with antineuronal antibodies. Conclusions: It is important to consider immune-mediated disorders in the differential diagnosis of rapidly progressive neurologic deficits. PMID:26601117

  7. Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Kuo, Amy L.; Wong, Katherine S.; Haman, Aissa; Devereux, Gillian; Raudabaugh, Benjamin J.; Johnson, David Y.; Torres-Chae, Charles C.; Finley, Ron; Garcia, Paul; Thai, Julie N.; Cheng, Hugo Q.; Neuhaus, John M.; Forner, Sven A.; Duncan, Jacque L.; Possin, Katherine L.; DeArmond, Stephen J.; Prusiner, Stanley B.; Miller, Bruce L.

    2013-01-01

    Objective: To determine whether oral quinacrine increases survival in sporadic Creutzfeldt-Jakob disease (sCJD). Methods: This NIH/National Institute on Aging–funded, double-blinded, placebo-controlled, stratified randomization treatment trial was conducted at the University of California, San Francisco from February 2005 through May 2009 (ClinicalTrials.gov, NCT00183092). Subjects were randomized (50:50) to quinacrine (300 mg daily) or placebo with inpatient evaluations at baseline, and planned for months 2, 6, and 12. Subjects returning for their month-2 visit were offered open-label quinacrine. The primary outcome was survival from randomization to month 2. Results: Of 425 patients referred, 69 subjects enrolled, 54 subjects were randomized to active drug or placebo, and 51 subjects with sCJD were included in survival analyses. Survival for the randomized portion of the trial (first 2 months) showed no significant difference between the 2 groups (log-rank statistic, p = 0.43; Cox proportional relative hazard = 1.43, quinacrine compared with placebo, 95% confidence interval = 0.58, 3.53). The quinacrine-treated group, however, declined less on 2 of 3 functional scales, the modified Rankin and Clinical Dementia Rating, than the placebo group during the first 2 months. Conclusion: This interventional study provides Class I evidence that oral quinacrine at 300 mg per day does not improve 2-month survival of patients with sCJD, compared with placebo. Importantly, this study shows that double-blinded, placebo-controlled, randomized treatment trials are possible in prion disease. Furthermore, the quantitative data collected on the course of sCJD will be useful for future trials. Classification of evidence: This study provides Class I evidence that quinacrine does not improve survival for people with sCJD when given orally at a dose of 300 mg per day for 2 months. PMID:24122181

  8. Clinical Trial Simulations Based on Genetic Stratification and the Natural History of a Functional Outcome Measure in Creutzfeldt-Jakob Disease.

    PubMed

    Mead, Simon; Burnell, Matthew; Lowe, Jessica; Thompson, Andrew; Lukic, Ana; Porter, Marie-Claire; Carswell, Christopher; Kaski, Diego; Kenny, Janna; Mok, Tze How; Bjurstrom, Nina; Franko, Edit; Gorham, Michele; Druyeh, Ronald; Wadsworth, Jonathan D F; Jaunmuktane, Zane; Brandner, Sebastian; Hyare, Harpreet; Rudge, Peter; Walker, A Sarah; Collinge, John

    2016-04-01

    A major challenge for drug development in neurodegenerative diseases is that adequately powered efficacy studies with meaningful end points typically require several hundred participants and long durations. Prion diseases represent the archetype of brain diseases caused by protein misfolding, the most common subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. There is no well-established trial method in prion disease. To establish a more powerful and meaningful clinical trial method in sCJD. A stratified medicine and simulation approach based on a prospective interval-cohort study conducted from October 2008 to June 2014. This study involved 598 participants with probable or definite sCJD followed up over 470 patient-years at a specialist national referral service in the United Kingdom with domiciliary, care home, and hospital patient visits. We fitted linear mixed models to the outcome measurements, and simulated clinical trials involving 10 to 120 patients (no dropouts) with early to moderately advanced prion disease using model parameters to compare the power of various designs. A total of 2681 assessments were done using a functionally orientated composite end point (Medical Research Council Scale) and associated with clinical investigations (brain magnetic resonance imaging, electroencephalography, and cerebrospinal fluid analysis) and molecular data (prion protein [PrP] gene sequencing, PrPSc type). Of the 598 participants, 273 were men. The PrP gene sequence was significantly associated with decline relative to any other demographic or investigation factors. Patients with sCJD and polymorphic codon 129 genotypes MM, VV, and MV lost 10% of their function in 5.3 (95% CI, 4.2-6.9), 13.2 (95% CI, 10.9-16.6), and 27.8 (95% CI, 21.9-37.8) days, respectively (P < .001). Simulations indicate that an adequately powered (80%; 2-sided α = .05) open-label randomized trial using 50% reduction in Medical Research Council Scale

  9. Risk of variant Creutzfeldt-Jakob disease in France.

    PubMed

    Chadeau-Hyam, Marc; Alpérovitch, Annick

    2005-02-01

    France has the second highest number of variant Creutzfeldt-Jakob disease (vCJD) cases worldwide. Imports of bovine carcasses from the UK probably constituted the main source of exposure of the French population to the bovine spongiform encephalopathy (BSE) agent. Meat products consumed whilst visiting the UK have also been considered as a possible source of exposure. We estimated the number of future vCJD cases in France using a simulation approach. Both the distribution of the vCJD incubation period and the age-dependent susceptibility to the BSE agent were estimated from UK data. The French epidemic was simulated by gender and birth-cohort from data on the infectivity of UK bovine tissues and simulations of the French consumption of infected beef products. We also used data on travel to the UK between 1980 and 1995. We predicted 33 future cases of vCJD: 12 in the 1940-69 birth-cohort and 21 in the post-1969 birth-cohort. No case was predicted in the pre-1940 cohort. Based on our model, simulated vCJD cases occurred later in the older (1940-69) than in the younger cohort (post-1969). Age at onset was stable in the post-1969 cohort and increased in the older cohort. The model predicted a small excess of male patients. No case was attributed to travels in the UK. This modelling confirms that a large vCJD epidemic in France is very unlikely. Since France (where 60% of the total British exports of bovine carcasses were exported) has been highly exposed to the BSE agent, our results are reassuring for most countries worldwide.

  10. [Presenile dementia (Creutzfeldt-Jakob disease). Clinical and experimental data on a newly reported case].

    PubMed

    Drăgănescu, N

    1988-01-01

    A newly recorded case of presenile dementia (Creutzfeldt-Jakob disease) is discussed. The disease is experimentally transmissible to guinea pigs, after a long incubation period. From a pathomorphological point of view the experimental disease in the guinea pig is characterized by spongiosis, proliferative glial reaction, disappearance of neurons and of Purkinje's cells.

  11. A Case of Sporadic Creutzfeldt-Jakob Disease Presenting as Conversion Disorder.

    PubMed

    Yegya-Raman, Nikhil; Aziz, Rehan; Schneider, Daniel; Tobia, Anthony; Leitch, Megan; Nwobi, Onyi

    2017-01-01

    Background. Creutzfeldt-Jakob disease is a rare disorder of the central nervous system. Its initial diagnosis may be obscured by its variable presentation. This case report illustrates the complexity of diagnosing this disease early in the clinical course, especially when the initial symptoms may be psychiatric. It offers a brief review of the literature and reinforces a role for consultation psychiatry services. Methods. PUBMED/MEDLINE was searched using the terms "Creutzfeldt-Jakob disease", "psychiatric symptoms", "conversion disorder", "somatic symptom disorder", "functional movement disorder", and "functional neurologic disorder". Case. The patient was a 64-year-old woman with no prior psychiatric history who was initially diagnosed with conversion disorder and unspecified anxiety disorder but soon thereafter was discovered to have Creutzfeldt-Jakob disease. Discussion. This case highlights the central role of psychiatric symptoms in early presentations of Creutzfeldt-Jakob disease. Still, few other cases in the literature report functional neurological symptoms as an initial sign. The consultation psychiatrist must remain alert to changing clinical symptoms, especially with uncharacteristic disease presentations.

  12. Lingering doubts about spongiform encephalopathy and Creutzfeldt-Jakob disease.

    PubMed

    Narang, H K

    2001-07-01

    Bovine spongiform encephalopathy (BSE) is an infectious disease and has been transmitted orally to many other animals, including humans. There is clear evidence of maternal transmission, although disagreement on the source of the BSE agent remains. The current theories link the origin of BSE to common scrapie in sheep. Twenty different strains of the scrapie agent have been isolated from sheep. A search of the literature indicates two distinct clinical syndromes in sheep, both of which have been called scrapie. I have designated these Type I (the common type), which exhibits itchiness and lose their wool, and Type II, which exhibits trembling and ataxia. Sheep inoculated with BSE develop Type II scrapie and they exhibit trembling. When cattle or mink are injected with the Type I strain, only a few will develop a clinical disease. By contrast, no clinical disease has so far been shown in cattle or mink by feeding them with Type I-infected sheep brains. However, either by injecting or feeding with the BSE strain, 100% of calves and mink develop the clinical disease. Evidence suggests that Type II is the cause of BSE. Identical clinical signs of Type II trembling are found in kuru and many of the recent cases of Creutzfeldt-Jakob disease. The BSE agent has caused spongiform encephalopathies (SEs) in domestic cats, tigers, and in some species of ruminants in zoos. The nature of the BSE agent remains unchanged when passaged through a range of species, irrespective of their genetic make up, demonstrating that variations in the host PrP gene are not a major factor in the susceptibility to the BSE agent. Since more than 85 zoo animals of many species have been diagnosed with SEs, from these studies it seems reasonable to conclude that the BSE agent can infect almost all mammalian species, including humans. For eradication of BSE and to reduce the risk of infection to humans, the development of a vaccine against BSE is suggested. Such a possibility should be fully explored.

  13. Prions in the urine of patients with variant Creutzfeldt-Jakob disease.

    PubMed

    Moda, Fabio; Gambetti, Pierluigi; Notari, Silvio; Concha-Marambio, Luis; Catania, Marcella; Park, Kyung-Won; Maderna, Emanuela; Suardi, Silvia; Haïk, Stéphane; Brandel, Jean-Philippe; Ironside, James; Knight, Richard; Tagliavini, Fabrizio; Soto, Claudio

    2014-08-07

    Prions, the infectious agents responsible for transmissible spongiform encephalopathies, consist mainly of the misfolded prion protein (PrP(Sc)). The unique mechanism of transmission and the appearance of a variant form of Creutzfeldt-Jakob disease, which has been linked to consumption of prion-contaminated cattle meat, have raised concerns about public health. Evidence suggests that variant Creutzfeldt-Jakob disease prions circulate in body fluids from people in whom the disease is silently incubating. To investigate whether PrP(Sc) can be detected in the urine of patients with variant Creutzfeldt-Jakob disease, we used the protein misfolding cyclic amplification (PMCA) technique to amplify minute quantities of PrP(Sc), enabling highly sensitive detection of the protein. We analyzed urine samples from several patients with various transmissible spongiform encephalopathies (variant and sporadic Creutzfeldt-Jakob disease and genetic forms of prion disease), patients with other degenerative or nondegenerative neurologic disorders, and healthy persons. PrP(Sc) was detectable only in the urine of patients with variant Creutzfeldt-Jakob disease and had the typical electrophoretic profile associated with this disease. PrP(Sc) was detected in 13 of 14 urine samples obtained from patients with variant Creutzfeldt-Jakob disease and in none of the 224 urine samples obtained from patients with other neurologic diseases and from healthy controls, resulting in an estimated sensitivity of 92.9% (95% confidence interval [CI], 66.1 to 99.8) and a specificity of 100.0% (95% CI, 98.4 to 100.0). The PrP(Sc) concentration in urine calculated by means of quantitative PMCA was estimated at 1×10(-16) g per milliliter, or 3×10(-21) mol per milliliter, which extrapolates to approximately 40 to 100 oligomeric particles of PrP(Sc) per milliliter of urine. Urine samples obtained from patients with variant Creutzfeldt-Jakob disease contained minute quantities of PrP(Sc). (Funded by the

  14. Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: background, evolution, and current concerns.

    PubMed Central

    Brown, P.; Will, R. G.; Bradley, R.; Asher, D. M.; Detwiler, L.

    2001-01-01

    The epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom, which began in 1986 and has affected nearly 200,000 cattle, is waning to a conclusion, but leaves in its wake an outbreak of human Creutzfeldt-Jakob disease, most probably resulting from the consumption of beef products contaminated by central nervous system tissue. Although averaging only 10-15 cases a year since its first appearance in 1994, its future magnitude and geographic distribution (in countries that have imported infected British cattle or cattle products, or have endogenous BSE) cannot yet be predicted. The possibility that large numbers of apparently healthy persons might be incubating the disease raises concerns about iatrogenic transmissions through instrumentation (surgery and medical diagnostic procedures) and blood and organ donations. Government agencies in many countries continue to implement new measures to minimize this risk. PMID:11266289

  15. Diagnosing Sporadic Creutzfeldt-Jakob Disease: Accuracy of CSF 14-3-3 Protein Test of the Spinal Fluid

    MedlinePlus

    ... JAKOB DISEASE: ACCURACY OF THE 14-3-3 PROTEIN TEST OF THE SPINAL FLUID This information sheet ... help you understand how the 14-3-3 protein test helps in diagnosing sporadic Creutzfeldt-Jakob disease ( ...

  16. Mad cow disease and Creutzfeldt-Jakob disease--is there a link?

    PubMed

    Rist, C E; Nielsen, J O

    1996-01-01

    The report of the Creutzfeldt-Jakob Surveillance Unit from March 1996 regarding 10 cases of a new variant of Creutzfeldt-Jakob disease (CJD) in young adults caused a great deal of uproar when it was suggested that a possible link with bovine spongiform encephalopathy (BSE) could not be excluded. BSE was first noticed in 1986 after the introduction of modified rendering systems in the manufacture of meat and bone meal containing animal wastes contaminated with scraple-like agents. This article reviews available information on CJD, BSE and other diseases caused by prions, transmission studies and the report of the CJD Surveillance Unit and discusses possible links between BSE and the new variant of CJD.

  17. [A Case of Sporadic Creutzfeldt-Jakob Disease That Developed With Psychiatric Symptoms].

    PubMed

    Özkan, Adile; Aydın Cantürk, İlknur; Candan, Fatma; Işık, Nihal; Özışık Karaman, Handan Işın

    2015-01-01

    Creutzfeldt-Jakob disease (CJD) is a fairly rare prion sickness characterized by rapidly progressive dementia and neuropsychiatric symptoms. The diversity of clinical characteristics of the disease causes difficulties during diagnosis. The first finding of the disease might be psychiatric symptoms. The male patient who was diagnosed with CJD after dementia, ataxia, and myoclonus developed rapidly following psychiatric symptoms, was presented in order to draw attention to the onset with psychiatric symptoms in CJD.

  18. Surveillance for Creutzfeldt-Jakob disease in Australia: update to December 2012.

    PubMed

    Klug, Genevieve M; Boyd, Alison; Zhao, Teresa; Stehmann, Christiane; Simpson, Marion; McLean, Catriona A; Masters, Colin L; Collins, Steven J

    2013-06-30

    Nation-wide surveillance for transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease (CJD) is undertaken by the Australian National Creutzfeldt-Jakob disease Registry (ANCJDR), based at the University of Melbourne. Surveillance has been undertaken since 1993. During this period the unit has evolved and adapted to changes in surveillance practices and requirements, the emergence of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness and understanding of CJD and other transmissible spongiform encephalopathies in the health care setting. In 2012, routine surveillance continued. This brief report provides an update on the surveillance data collected by the ANCJDR prospectively from 1993 to December 2012, and retrospectively to 1970. It also highlights the recent release of the revised Australian CJD Infection Control Guidelines.

  19. A practical approach to avoiding iatrogenic Creutzfeldt-Jakob disease (CJD) from invasive instruments.

    PubMed

    Brown, Paul; Farrell, Michael

    2015-07-01

    Potential Creutzfeldt-Jakob disease instrument-contamination events continue to occur, causing widespread hospital and patient concern. We propose the use of a combination of diagnostic tests (ie, spinal fluid for 14-3-3 protein or nasal brushing for misfolded prion protein) and instrument handling procedures (ie, using a regional set of dedicated instruments), which if applied to all patients admitted with symptoms of either dementia or cerebellar disease, should eliminate the risk of iatrogenic instrument infection.

  20. Atypical presentation of Creutzfeldt-Jakob disease: a rare but important cause of rapidly progressive dementia.

    PubMed

    Taillefer, Marguerite S; Tangarorang, Glendo L; Kuchel, George A; Menkes, Daniel L

    2011-09-01

    We report an atypical presentation of sporadic Creutzfeldt-Jakob disease (CJD) in a 74-year-old woman that illustrates the difficulty in diagnosing this rare, but important, cause of rapidly progressive dementia. Despite well-established criteria, this diagnosis is often missed or substantially delayed (Table 1). In this case, a precipitous cognitive decline associated with a urinary tract infection initiallysuggested delirium. Although atypical CJD was considered as a cause when symptoms persisted, a definitive diagnosis was established postmortem when the cerebrospinal fluid (CSF) prion protein 14-3-3 tested positive. Creutzfeldt-Jakob disease must be considered in the differential diagnosis of rapidly progressive dementia as Connecticut accounts for approximately three of the more than 200 cases diagnosed nationally.

  1. Symptomatic aggravation after corticosteroid pulse therapy in definite sporadic Creutzfeldt-Jakob disease with the feature of Hashimoto's encephalopathy.

    PubMed

    Jang, Jae-Won; Park, So Young; Park, Young Ho; Kim, Jung E; Kim, SangYun

    2014-09-08

    Creutzfeldt-Jakob disease and Hashimoto's encephalopathy often show similar clinical presentation. Among Creutzfeldt-Jakob disease mimics, Hashimoto's encephalopathy is particularly important as it is treatable with corticosteroids. Thus, in cases of middle-aged woman diagnosed with probable Creutzfeldt-Jakob disease and who exhibit high titers of antithyroid antibodies, corticosteroid pulse therapy is typically performed with expectations of near complete recovery from Hashimoto's encephalopathy. Herein, we provide the first case report that exhibited a negative effect of corticosteroid pulse therapy for a patient with Creutzfeldt-Jakob disease with features of Hashimoto's encephalopathy. We report a case of 59-year-old Asian woman with blurred vision, dysarthria, myoclonus, and rapidly progressive dementia. Cerebrospinal fluid showed 14-3-3 protein positive. Electroencephalogram showed periodic sharp waves (1.5 Hz) at the bilateral frontal or occipital areas. Magnetic resonance imaging showed high signal intensities at the bilateral cerebral cortex, caudate nucleus, and putamen. The patient was diagnosed with probable Creutzfeldt-Jakob disease. However, serum analysis showed a high titer of antithyroid antibodies. We started corticosteroid pulse therapy with subsequent aggravation of seizure activity including generalized myoclonus, epilepsia parialis continua, and ballistic dyskinesia, which was effectively treated with clonazepam. We provide evidence of a case of Creutzfeldt-Jakob disease that exhibited clinical deterioration after corticosteroid therapy. Although histopathological confirmation with brain biopsy is not easily available in Creutzfeldt-Jakob disease patients, selective initiation of corticosteroid pulse therapy should be considered in cases of uncertain diagnosis for differentiation with Hashimoto's encephalopathy.

  2. Prion infectivity in the spleen of a PRNP heterozygous individual with subclinical variant Creutzfeldt-Jakob disease.

    PubMed

    Bishop, Matthew T; Diack, Abigail B; Ritchie, Diane L; Ironside, James W; Will, Robert G; Manson, Jean C

    2013-04-01

    Blood transfusion has been identified as a source of human-to-human transmission of variant Creutzfeldt-Jakob disease. Three cases of variant Creutzfeldt-Jakob disease have been identified following red cell transfusions from donors who subsequently developed variant Creutzfeldt-Jakob disease and an asymptomatic red cell transfusion recipient, who did not die of variant Creutzfeldt-Jakob disease, has been identified with prion protein deposition in the spleen and a lymph node, but not the brain. This individual was heterozygous (MV) at codon 129 of the prion protein gene (PRNP), whereas all previous definite and probable cases of variant Creutzfeldt-Jakob disease have been methionine homozygotes (MM). A critical question for public health is whether the prion protein deposition reported in peripheral tissues from this MV individual correlates with infectivity. Additionally it is important to establish whether the PRNP codon 129 genotype has influenced the transmission characteristics of the infectious agent. Brain and spleen from the MV blood recipient were inoculated into murine strains that have consistently demonstrated transmission of the variant Creutzfeldt-Jakob disease agent. Mice were assessed for clinical and pathological signs of disease and transmission data were compared with other transmission studies in variant Creutzfeldt-Jakob disease, including those on the spleen and brain of the donor to the index case. Transmission of variant Creutzfeldt-Jakob disease was observed from the MV blood recipient spleen, but not from the brain, whereas there was transmission from both spleen and brain tissues from the red blood cell donor. Longer incubation times were observed for the blood donor spleen inoculum compared with the blood donor brain inoculum, suggesting lower titres of infectivity in the spleen. The distribution of vacuolar pathology and abnormal prion protein in infected mice were similar following inoculation with both donor and recipient spleen

  3. Ataxic Creutzfeldt-Jakob disease: diagnostic techniques and neuropathologic observations in early disease.

    PubMed

    Jones, H R; Hedley-Whyte, E T; Freidberg, S R; Baker, R A

    1985-02-01

    We studied two cases of ataxic Creutzfeldt-Jakob disease. EEG, CT, evoked responses, and CSF were normal in one purely ataxic patient. Diagnosis was established by cerebellar biopsy. Autopsy demonstrated devastating spongiform changes in the cerebellum, basal ganglia, and thalamus with rare focal changes in cerebral cortex. In the second patient, late generalized changes developed with dementia. Diagnostic studies included abnormal visual evoked responses, CSF with abnormal oligoclonal bands and IgG, and subacute spongiform encephalopathy in frontal lobe biopsy. Early diagnosis is best established by biopsy of brain areas most likely to be involved on the basis of clinical neurologic findings.

  4. On the Question of Sporadic or Atypical Bovine Spongiform Encephalopathy and Creutzfeldt-Jakob Disease

    PubMed Central

    McShane, Lisa M.; Zanusso, Gianluigi; Detwiler, Linda

    2006-01-01

    Strategies to investigate the possible existence of sporadic bovine spongiform encephalopathy (BSE) require systematic testing programs to identify cases in countries considered to have little or no risk of orally acquired disease or to detect a stable occurrence of atypical cases in countries in which orally acquired disease is disappearing. To achieve 95% statistical confidence that the prevalence for sporadic BSE is no greater than 1 per million (i.e., the annual incidence of sporadic Creutzfeldt-Jakob disease [CJD] in humans) would require negative tests in 3 million randomly selected older cattle. A link between BSE and sporadic CJD has been suggested on the basis of laboratory studies but is unsupported by epidemiologic observation. Such a link might yet be established by the discovery of a specific molecular marker or of particular combinations of trends over time of typical and atypical BSE and various subtypes of sporadic CJD, as their numbers are influenced by a continuation of current public health measures that exclude high-risk bovine tissues from the animal and human food chains. PMID:17326930

  5. Creutzfeldt-Jakob disease segregating in a three generation Danish family.

    PubMed

    Holm, I E; Abelskov, K; Bojsen-Møller, M; Nielsen, A L; Jørgensen, A L

    2001-03-01

    A three generation family is presented in which rapidly progressive, early-onset Creutzfeldt-Jakob disease without typical EEG changes segregates as an autosomal dominant disease. An aspartic acid to asparagine mutation at codon 178 of the prion gene, PRNP, co-segregates with the disease. As expected, the disease allele also carries the valine codon of the polymorphic valine/methionine codon 129 of the gene. In family members homozygous for this valine codon the disease was more rapidly progressive than in a heterozygous family member, who had a variant clinical phenotype. Definite neuropathological diagnosis required prion staining with specific antibodies.

  6. Psychiatric presentation of sporadic Creutzfeldt-Jakob disease: a challenge to current diagnostic criteria.

    PubMed

    Ali, Rehiana; Baborie, Atik; Larner, Andrew J; White, Richard

    2013-01-01

    Pathological diagnosis remains the gold standard for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), but being able to differentiate between CJD and non-prion diseases clinically is important because many of the non-prion, rapidly progressive dementias are treatable. Diagnostic criteria need both high sensitivity and specificity while remaining applicable to clinical practice. Despite extensive updates to the clinical criteria for sCJD, there remains a heavy emphasis on neurological signs. We describe a psychiatric presentation of sCJD that did not fulfill the diagnostic criteria until very late in a prolonged disease course and required biopsy for diagnosis.

  7. Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Forner, Sven A.; Takada, Leonel T.; Bettcher, Brianne M.; Lobach, Iryna V.; Tartaglia, Maria Carmela; Torres-Chae, Charles; Haman, Aissatou; Thai, Julie; Vitali, Paolo; Neuhaus, John; Bostrom, Alan; Miller, Bruce L.; Rosen, Howard J.

    2015-01-01

    Summary We assessed the diagnostic utility of 3 CSF biomarkers—14-3-3 protein, total tau (T-tau), and neuron-specific enolase (NSE)—from the same lumbar puncture to distinguish between participants with neuropathologically confirmed sporadic Creutzfeldt-Jakob disease (sCJD, n = 57) and controls with nonprion rapidly progressive dementia (npRPD, n = 41). Measures of diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value, as well as logistic regression and area under the receiver operator curve (AUC), were used to assess the ability of these CSF biomarkers, alone or concomitantly, to predict diagnosis. In a subcohort with available MRI (sCJD n = 57, npRPD = 32), we compared visual assessment of diffusion-weighted imaging MRI sequences to these CSF biomarkers. MRI was the best predictor, with an AUC of 0.97 (confidence interval [CI] 0.92–1.00) and a diagnostic accuracy of 97% (CI 90%–100%). Of the CSF biomarkers, T-tau had a higher diagnostic accuracy (79.6%) than 14-3-3 (70.4%, CI for difference 8.7%, 9.7%; p = 0.048) or NSE (71.4%, CI for difference 7.6%, 8.7%; p = 0.03). PMID:26137420

  8. Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease.

    PubMed

    Forner, Sven A; Takada, Leonel T; Bettcher, Brianne M; Lobach, Iryna V; Tartaglia, Maria Carmela; Torres-Chae, Charles; Haman, Aissatou; Thai, Julie; Vitali, Paolo; Neuhaus, John; Bostrom, Alan; Miller, Bruce L; Rosen, Howard J; Geschwind, Michael D

    2015-04-01

    We assessed the diagnostic utility of 3 CSF biomarkers-14-3-3 protein, total tau (T-tau), and neuron-specific enolase (NSE)-from the same lumbar puncture to distinguish between participants with neuropathologically confirmed sporadic Creutzfeldt-Jakob disease (sCJD, n = 57) and controls with nonprion rapidly progressive dementia (npRPD, n = 41). Measures of diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value, as well as logistic regression and area under the receiver operator curve (AUC), were used to assess the ability of these CSF biomarkers, alone or concomitantly, to predict diagnosis. In a subcohort with available MRI (sCJD n = 57, npRPD = 32), we compared visual assessment of diffusion-weighted imaging MRI sequences to these CSF biomarkers. MRI was the best predictor, with an AUC of 0.97 (confidence interval [CI] 0.92-1.00) and a diagnostic accuracy of 97% (CI 90%-100%). Of the CSF biomarkers, T-tau had a higher diagnostic accuracy (79.6%) than 14-3-3 (70.4%, CI for difference 8.7%, 9.7%; p = 0.048) or NSE (71.4%, CI for difference 7.6%, 8.7%; p = 0.03).

  9. Sporadic Creutzfeldt-Jakob disease (sCJD) with asymmetric findings.

    PubMed

    Khilari, Madhuri; Chakkalakkoombil, Sunitha Vellathussery; Wadwekar, Vaibhav; Nair, Pradeep Pankajakshan

    2014-03-24

    We report a case of a patient with probable Creutzfeldt-Jakob disease (CJD) who had psychiatric manifestation in the form of withdrawn depressive behaviour at the onset, followed by rapidly progressive ataxia, parkinsonism, mutism and cognitive decline with generalised asynchronous multifocal myoclonic jerks. His EEG exhibited focal (lateralised) periodic triphasic sharp waves on the background of generalised delta slowing, which later on became more generalised. MRI of the brain showed hyperintensity in basal ganglia with cortical ribbon sign in bilateral frontal region. Clinical course showed progressive deterioration to an akinetic-abulic stage. He died 2 months after the onset of symptoms.

  10. [Delayed diagnosis in a patient with Creutzfeldt-Jakob disease in a psychiatric hospital].

    PubMed

    Roest, S; Mestdagh, I; de Grave, C; Pals, P

    2016-01-01

    A 51-year-old female teacher of dance was referred to the diagnostic unit of our psychiatric hospital with symptoms of anxiety and depression. The clinical image was suggestive of organic pathology, but this could not be determined with certainty until a late stage. We discuss the course of the patient's illness. Her symptoms appeared to be psychiatric and closely resembled those of Creutzfeldt-Jakob disease. We comment on some of the signs that could have led to an earlier diagnosis and we discuss the tools that are needed.

  11. Creutzfeldt-Jakob disease with a codon 210 mutation: first pathological observation in a Japanese patient.

    PubMed

    Tajima, Yasutaka; Satoh, Chika; Mito, Yasunori; Kitamoto, Tetsuyuki

    2014-01-01

    We herein report a case of Creutzfeldt-Jakob disease (CJD) with a V210I mutation and discuss the pathological findings. The patient's clinical course was quite similar to that of patients with sporadic CJD. Diffusion-weighted magnetic resonance imaging (MRI) disclosed a high signal intensity in the basal ganglia and cerebral cortices. Pathologically, spongiform degeneration of neurons and their processes with reactive astrocytosis was observed. Prion protein immunostaining revealed diffuse positive and plaque-type patterns. Only one Japanese case of CJD with this type of mutation has been reported to date, but without any pathological examination results. Therefore, this report is considered to be highly significant for understanding CJD.

  12. Risk of transmission of Creutzfeldt-Jakob disease via blood and blood products. The French risk-analysis over the last 15 years.

    PubMed

    Martin, M; Trouvin, J-H

    2013-09-01

    Risk of transmission of Creutzfeldt-Jakob disease (infectious agent, responsible of spongiform encephalopathy) via blood and blood components (including the plasma-derived medicinal products such as coagulation factors and immunoglobulins) have been a subject of concern for Health authorities since the early 1980s, with a regain of interest in the 1990s, with the bovine spongiform encephalopathy outbreak followed few years after with the notification of the first cases of variant Creutzfeldt-Jakob disease in humans. The risk-analysis and measures taken by the French authorities in the period 1990-2010 will be described with the various assumptions and working hypothesis used and revisited as new findings become available.

  13. Implications for Creutzfeldt-Jakob disease (CJD) in dentistry: a review of current knowledge.

    PubMed

    Walker, J T; Dickinson, J; Sutton, J M; Marsh, P D; Raven, N D H

    2008-06-01

    This review explores our current understanding of the risks of (variant) Creutzfeldt-Jakob disease transmission via dental practice, and whether they merit the rigorous enforcement of improved standards of instrument cleaning and decontamination. The recognition of prions as novel infectious agents in humans has caused significant concern among the public and medical professionals alike. Creutzfeldt-Jakob disease (CJD) in humans has been shown to be transmissible via several routes, including transplantation, contaminated medical products, and via neurosurgery. While the likelihood of transmission via dentistry is undoubtedly very low, this may be amplified considerably by unknown risk factors, such as disease prevalence (particularly in the UK), altered tissue distribution of vCJD, and the failure of decontamination processes to address the inactivation of prions adequately. Since current diagnostic techniques are unable to detect PrP(Sc) in human dental tissues, there is limited evidence for the presence of infectivity. Given these uncertainties, the control of risk by reinforced and improved decontamination practices seems the most appropriate response.

  14. Sporadic Creutzfeldt-Jakob disease in a native Puerto Rican patient.

    PubMed

    Del Pilar-Morales, Esteban A; Cali, Ignazio; Chapas, Javier; Bertrán-Pasarell, Jorge; Puoti, Gianfranco; Gambetti, Pierluigi; Nobo, Ulises

    2015-03-01

    The diagnosis of Creutzfeldt-Jakob disease (CJD) is often a challenge for most physicians given its extremely low incidence and different clinico-pathological presentations. We report the case of a 56-year old patient native to Puerto Rico suspected of sporadic Creutzfeldt-Jakob disease (sCD). The symptoms at onset were notorious for bilateral cortical blindness followed by rapidly progressive cognitive decline, visual deficit, increased levels of CSF 14-3-3 and tau along with positive brain MRI and EEG, are highly indicative of CJD. The definite diagnosis was confirmed by the National Prion Disease Pathology Surveillance Center (NPDPSC), in Cleveland, Ohio, USA. Lack of genetic mutations in the prion protein (PrP) gene, widespread histopathological changes and the accumulation of scrapie PrP (PrPSc) in the brain confirmed the diagnosis of sCJD. The patient, admitted to our institution in 2011, represents the first detailed report of sCJD in a native Puerto Rican patient living in Puerto Rico.

  15. Sporadic Creutzfeldt-Jakob Disease With Unilateral Symptoms in the Setting of Metastatic Renal Cell Carcinoma.

    PubMed

    Rossi, Kyle C; Stahl, Christine M; Zhang, Pengfei; Liang, John W; Marcuse, Lara V; Lublin, Fred

    2017-07-01

    Although it is not rare for magnetic resonance imaging findings in Creutzfeldt-Jakob disease to be asymmetric, unilateral clinical syndromes are uncommonly reported and may confound diagnosis. In addition, neurological paraneoplastic syndromes are not common in renal cell carcinoma, though there are cases reported, often without an offending antibody isolated. A 66-year-old man was admitted with 1 month of left-sided numbness and "loss of control" of the left arm. Examination revealed action-induced irregular jerking movements of the left arm. Mental status testing was normal. Magnetic resonance imaging brain revealed patchy areas of restricted diffusion along the cerebral cortices. Screening computed tomographic scans revealed innumerable lung nodules compatible with metastases, as well as a renal mass consistent with renal cell carcinoma. Lumbar puncture was performed and cerebrospinal fluid was sent for paraneoplastic autoantibody evaluation and protein 14-3-3. Over the next week the patient developed dystonic posturing of the left arm, left leg jerking movements, a right arm action tremor, and cognitive impairment. Paraneoplastic autoantibodies were negative. Protein 14-3-3 was elevated and brain biopsy revealed spongiform encephalopathy with positive immunoblotting. The patient died about 2 months from symptom onset. Creutzfeldt-Jakob disease can present with entirely unilateral myoclonus and numbness, without specific complaints of cognitive impairment. Not every difficult or unclear neurological syndrome in a patient with metastatic cancer is a paraneoplastic syndrome.

  16. Enhanced geographically restricted surveillance simulates sporadic Creutzfeldt-Jakob disease cluster.

    PubMed

    Klug, Genevieve M; Wand, Handan; Boyd, Alison; Law, Matthew; Whyte, Scott; Kaldor, John; Masters, Colin L; Collins, Steven

    2009-02-01

    Spatio-temporal clustering of sporadic Creutzfeldt-Jakob disease (sCJD) has been recognized and investigated previously in various global settings including Australia. Generally, despite often extensive investigation, explanations such as point source outbreaks and plausible case-to-case transmission links have not been identified to explain the apparently higher case rates than expected. In the context of national surveillance during the period 1993-2006, an increased number of cases of sCJD were recognized in a circumscribed coastal region of eastern Australia. To assess the significance of this apparent clustering, the Spatial Scan Statistic was used to examine for geographic excess of CJD mortality at spatial and temporal combined, spatial only and temporal only levels. A significant spatial cluster was confirmed, encompassing three contiguous statistical local areas within the state of New South Wales (NSW). Detailed epidemiological analysis did not reveal a plausible cross-over or point source transmission event. Further evaluation prompted the conclusion that vigilant and motivated managing clinicians in this geographically circumscribed area of NSW evinced a sustained higher level of clinical awareness for the broad phenotypic spectrum of CJD with reliable referral of suspect cases for further investigation. In addition, these physicians established and maintained a well-coordinated and active approach to suspect CJD autopsy. This combination of factors translated into a higher intensity of surveillance at approximately twice the rate per population observed in the entire state, culminating in twice the incidence of sCJD at around 2.28 cases/million population/year. The hypothesis that intensity of surveillance for rare disorders can be objectively measured and that this can positively correlate with disease incidence deserves further exploration. It may prove to be an important insight into the varying incidence rates over periods of time within individual

  17. Cerebrospinal Fluid Biomarkers in the Diagnosis of Creutzfeldt-Jakob Disease in Slovak Patients: over 10-Year Period Review.

    PubMed

    Koscova, Silvia; Zakova Slivarichova, Dana; Tomeckova, Ivana; Melicherova, Katarina; Stelzer, Martin; Janakova, Alzbeta; Kosorinova, Dana; Belay, Girma; Mitrova, Eva

    2016-09-24

    Creutzfeldt-Jakob disease is a rare, but rapidly progressive, up to now untreatable and fatal neurodegenerative disorder. Clinical diagnosis of Creutzfeldt-Jakob disease (CJD) is difficult; however, it can be facilitated by suitable biomarkers. Aim of the present study is to compare levels of cerebrospinal fluid biomarkers (total tau protein, phosphorylated-tau protein, protein 14-3-3 and amyloid beta) in Slovak population of CJD suspect cases, retrospectively in over a 10-year period. One thousand three hundred sixty-four CSF samples from patients with suspect CJD, forming a homogenous group in terms of geographical as well as of equal transport conditions, storage and laboratory processing, were analysed. Definite diagnosis of Creutzfeldt-Jakob disease was confirmed in 101 patients with genetic form, and 60 patients with its sporadic form of the disease. Specificity of protein 14-3-3 and total tau in both forms CJD was similar (87 % for P14-3-3/85 % for total tau), sensitivity to P 14-3-3 and total tau was higher in sporadic Creutzfeldt-Jakob disease (sCJD) (90/95 %) than in genetic Creutzfeldt-Jakob disease (gCJD) (89/74 %). As expected, the total tau levels were significantly higher in CJD patients than in controls, but there was also significant difference between gCJD and sCJD (levels in gCJD were lower; p = 0.003). There was no significant difference in p-tau and Aβ 1-42 levels neither between both CJD forms nor between CJD patients and control group.

  18. Variant Creutzfeldt-Jakob disease in the United Kingdom: a countrywide or local risk?

    PubMed

    Molesworth, Anna M; Cousens, Simon N; Noel, Gill O; Ward, Hester J T

    2010-07-01

    The aim of this study was to identify factors that may have augmented local risks for variant Creutzfeldt-Jakob disease (vCJD). A descriptive study was conducted of local investigations of UK cases of vCJD, who had lived close together at some point since 1980. The main outcome measures were domestic, educational, occupational, healthcare associated, social and recreational links between cases; common dietary, iatrogenic and other possible routes of exposure to vCJD infection; and locally elevated vCJD risk. A cluster of five cases of vCJD in a rural area in North Leicestershire was investigated in 2000 (p=0.004). A further 12 investigations of geographically associated cases of vCJD have been undertaken in the UK. In nine of the 12 locations, some or all of the local cases had consumed beef purchased from the same local retail outlets or provided by a common supplier of school meals, or had some aspect of their medical-dental care in common. In only three of these locations were circumstances identified where the local risk of transmission might have been elevated. In none of the locations was there strong evidence to exclude chance as a likely explanation for the local occurrence of these vCJD cases. Although it is possible that in some parts of the UK local factors may have increased the risk of acquiring vCJD, most cases that were geographically close to each other are most likely due to the same factors that gave rise to the large majority of other vCJD cases in the UK.

  19. Voltage-Gated Potassium Channel Autoimmunity Mimicking Creutzfeldt-Jakob Disease

    PubMed Central

    Geschwind, Michael D.; Tan, K. Meng; Lennon, Vanda A.; Barajas, Ramon F.; Haman, Aissa; Klein, Christopher J.; Josephson, S. Andrew; Pittock, Sean J.

    2009-01-01

    Background Rapidly progressive dementia has a variety of causes, including Creutzfeldt-Jakob disease (CJD) and neuronal voltage-gated potassium channel (VGKC) autoantibody–associated encephalopathy. Objective To describe patients thought initially to have CJD but found subsequently to have immunotherapy-responsive VGKC autoimmunity. Design Observational, prospective case series. Setting Department of Neurology, Mayo Clinic, and the Memory and Aging Center, University of California, San Francisco. Patients A clinical serologic cohort of 15 patients referred for paraneoplastic autoantibody evaluation. Seven patients were evaluated clinically by at least one of us. Clinical information for the remaining patients was obtained by physician interview or medical record review. Main Outcome Measures Clinical features, magnetic resonance imaging abnormalities, electroencephalographic patterns, cerebrospinal fluid analyses, and responses to immunomodulatory therapy. Results All the patients presented subacutely with neurologic manifestations, including rapidly progressive dementia, myoclonus, extrapyramidal dysfunction, visual hallucinations, psychiatric disturbance, and seizures; most (60%) satisfied World Health Organization diagnostic criteria for CJD. Magnetic resonance imaging abnormalities included cerebral cortical diffusion-weighted imaging hyperintensities. Electroencephalographic abnormalities included diffuse slowing, frontal intermittent rhythmic delta activity, and focal epileptogenic activity but not periodic sharp wave complexes. Cerebrospinal fluid 14-3-3 protein or neuron-specific enolase levels were elevated in 5 of 8 patients. Hyponatremia was common (60%). Neoplasia was confirmed histologically in 5 patients (33%) and was suspected in another 5. Most patients’ conditions (92%) improved after immunomodulatory therapy. Conclusions Clinical, radiologic, electrophysiologic, and laboratory findings in VGKC autoantibody–associated encephalopathy may be

  20. A case cluster of variant Creutzfeldt-Jakob disease linked to the Kingdom of Saudi Arabia.

    PubMed

    Coulthart, Michael B; Geschwind, Michael D; Qureshi, Shireen; Phielipp, Nicolas; Demarsh, Alex; Abrams, Joseph Y; Belay, Ermias; Gambetti, Pierluigi; Jansen, Gerard H; Lang, Anthony E; Schonberger, Lawrence B

    2016-10-01

    As of mid-2016, 231 cases of variant Creutzfeldt-Jakob disease-the human form of a prion disease of cattle, bovine spongiform encephalopathy-have been reported from 12 countries. With few exceptions, the affected individuals had histories of extended residence in the UK or other Western European countries during the period (1980-96) of maximum global risk for human exposure to bovine spongiform encephalopathy. However, the possibility remains that other geographic foci of human infection exist, identification of which may help to foreshadow the future of the epidemic. We report results of a quantitative analysis of country-specific relative risks of infection for three individuals diagnosed with variant Creutzfeldt-Jakob disease in the USA and Canada. All were born and raised in Saudi Arabia, but had histories of residence and travel in other countries. To calculate country-specific relative probabilities of infection, we aligned each patient's life history with published estimates of probability distributions of incubation period and age at infection parameters from a UK cohort of 171 variant Creutzfeldt-Jakob disease cases. The distributions were then partitioned into probability density fractions according to time intervals of the patient's residence and travel history, and the density fractions were combined by country. This calculation was performed for incubation period alone, age at infection alone, and jointly for incubation and age at infection. Country-specific fractions were normalized either to the total density between the individual's dates of birth and symptom onset ('lifetime'), or to that between 1980 and 1996, for a total of six combinations of parameter and interval. The country-specific relative probability of infection for Saudi Arabia clearly ranked highest under each of the six combinations of parameter × interval for Patients 1 and 2, with values ranging from 0.572 to 0.998, respectively, for Patient 2 (age at infection × lifetime) and

  1. Creutzfeldt-Jakob disease latest unknown in struggle to restore faith in blood supply.

    PubMed Central

    Vaughan, P

    1996-01-01

    There was considerable medical interest in a recent Toronto conference on prion disease--and in Creutzfeldt-Jakob disease (CJD) in particular--because of the recent tainted-beef controversy in Britain. Although there is no proven link between a newly recognized variant form of CJD and "mad cow disease," and no evidence that CJD can be spread through the blood supply, the theoretical risk has scientists scrambling to understand how the disease is spread and policymakers struggling with the thorny issue of whether to notify persons who have received blood or blood products that may place them at risk. Until the mysteries of prion diseases and their transmission are unravelled, Dr. Peter Vaughan reports, physicians and their patients will have to live with uncertainty. Images p566-a PMID:8804263

  2. Distribution and Quantitative Estimates of Variant Creutzfeldt-Jakob Disease Prions in Tissues of Clinical and Asymptomatic Patients

    PubMed Central

    Douet, Jean Y.; Lacroux, Caroline; Aron, Naima; Head, Mark W.; Lugan, Séverine; Tillier, Cécile; Huor, Alvina; Cassard, Hervé; Arnold, Mark; Beringue, Vincent; Ironside, James W.

    2017-01-01

    In the United-Kingdom, ≈1 of 2,000 persons could be infected with variant Creutzfeldt-Jakob disease (vCJD). Therefore, risk of transmission of vCJD by medical procedures remains a major concern for public health authorities. In this study, we used in vitro amplification of prions by protein misfolding cyclic amplification (PMCA) to estimate distribution and level of the vCJD agent in 21 tissues from 4 patients who died of clinical vCJD and from 1 asymptomatic person with vCJD. PMCA identified major levels of vCJD prions in a range of tissues, including liver, salivary gland, kidney, lung, and bone marrow. Bioassays confirmed that the quantitative estimate of levels of vCJD prion accumulation provided by PMCA are indicative of vCJD infectivity levels in tissues. Findings provide critical data for the design of measures to minimize risk for iatrogenic transmission of vCJD. PMID:28518033

  3. [Perioperative considerations for performing a brain biopsy on a patient with subtype VV2 sporadic Creutzfeldt-Jakob disease].

    PubMed

    Guerrero-Domínguez, R; Rubio-Romero, R; González-González, G; Jiménez, I

    2015-04-01

    Creutzfeldt-Jakob disease (CJD) is the most common transmissible spongiform encephalopathy. It is an infectious, progressive, degenerative neurological disorder, with a presumably long incubation period, but a rapid fatal course. CJD is transmitted by a proteinaceous infectious agent, or «prion». Because the prions are difficult to eradicate and are resistant to the currently used sterilization methods, special precautions must be taken with all surgical instruments. It is recommended the single-use equipment, destruction of contaminated equipment, decontamination of reusable instruments, use of protective clothing, and storing and quarantining surgical instruments. The single-use equipment and some tissues and body fluids from the patient with CJD are highly infectious and must be incinerated. We report a case of a patient who had undergone brain biopsy for suspected of CJD, being confirmed to have sporadic CJD. Specific preventive measures were taken to reduce the risk of transmission to healthcare workers.

  4. Variant Creutzfeldt-Jakob Disease (vCJD)

    MedlinePlus

    ... that was first described in 1996 in the United Kingdom. There is now strong scientific evidence that the agent responsible for the outbreak of prion disease in cows, bovine spongiform encephalopathy (BSE or 'mad cow' disease), is the ... vCJD case in the United States. More E-Mail Us For Questions or ...

  5. Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Kallenberg, K.; Summers, D. M.; Romero, C.; Taratuto, A.; Heinemann, U.; Breithaupt, M.; Varges, D.; Meissner, B.; Ladogana, A.; Schuur, M.; Haik, S.; Collins, S. J.; Jansen, Gerard H.; Stokin, G. B.; Pimentel, J.; Hewer, E.; Collie, D.; Smith, P.; Roberts, H.; Brandel, J. P.; van Duijn, C.; Pocchiari, M.; Begue, C.; Cras, P.; Will, R. G.; Sanchez-Juan, P.

    2009-01-01

    Several molecular subtypes of sporadic Creutzfeldt–Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt–Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt–Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt–Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt–Jakob disease. Patients with sporadic Creutzfeldt–Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as ‘suspected sporadic Creutzfeldt–Jakob disease’ but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt–Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt–Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic

  6. Sporadic Creutzfeldt-Jakob Disease in 2 Plasma Product Recipients, United Kingdom.

    PubMed

    Urwin, Patrick; Thanigaikumar, Kumar; Ironside, James W; Molesworth, Anna; Knight, Richard S; Hewitt, Patricia E; Llewelyn, Charlotte; Mackenzie, Jan; Will, Robert G

    2017-06-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) has not been previously reported in patients with clotting disorders treated with fractionated plasma products. We report 2 cases of sCJD identified in the United Kingdom in patients with a history of extended treatment for clotting disorders; 1 patient had hemophilia B and the other von Willebrand disease. Both patients had been informed previously that they were at increased risk for variant CJD because of past treatment with fractionated plasma products sourced in the United Kingdom. However, both cases had clinical and investigative features suggestive of sCJD. This diagnosis was confirmed in both cases on neuropathologic and biochemical analysis of the brain. A causal link between the treatment with plasma products and the development of sCJD has not been established, and the occurrence of these cases may simply reflect a chance event in the context of systematic surveillance for CJD in large populations.

  7. Variant Creutzfeldt-Jakob disease--a problem for general dental practitioners?

    PubMed

    Whitworth, Christine L

    2002-07-01

    Over a hundred deaths from variant Creutzfeldt-Jakob disease (vCJD) have now been recorded. The incubation period for vCJD may be up to 40 years and the number of asymptomatic carriers in the population could be as many as 100,000. Confirmed iatrogenic transmission of other human transmissible spongiform encephalopathies raises the possibility of cross-infection from apparently healthy persons who are incubating vCJD. Decontamination techniques routinely used in general dental practice are incapable of inactivating the infective protein responsible for transmitting the disease. So far, no evidence exists to preclude the risk of iatrogenic infection occurring during dental procedures. The author reviews present knowledge of the infective agent, its transmissibility, its origins, current guidelines and the implications for dental practice.

  8. [Acquired Creutzfeldt-Jakob disease (CJD)--Kuru, iatrogenic CJD, variant CJD].

    PubMed

    Sanjo, Nobuo

    2007-08-01

    Human prion diseases can be classified as sporadic, hereditary or acquired. The acquired forms are known to be caused by the transmission to human from human or animal, via medical appliances, oral intake or parenteral solutions. Usually, peripheral infection such as oral(Kuru) or parenteral (human pituitary hormones) transmission causes cerebellar degenerative form, and central nervous system infection such as neurosurgical treatment, dura mater grafts or corneal grafts transmission causes clinical features similar to sporadic form of Creutzfeldt-Jakob disease (CJD). The variant CJD (vCJD) is considered to be transmitted bovine spongiform encephalopathy(BSE) to human through dietary exposure. The early clinical features of vCJD are dominated by psychiatric symptoms, and minor number of patients have neurological symptoms from the onset. After about 6 months, there are frank neurological signs, including ataxia, cognitive impairment and involuntary movements.

  9. A Case Report of Probable Sporadic Creutzfeldt-Jakob Disease: How to Approach Early Diagnosis?

    PubMed

    Tan, Bowei; Morales Mangual, Carlos; Mahmud, Iftekhar; Tongo, Nosakhare D; Mararenko, Larisa; Kay, Arthur

    2017-05-30

    Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare and fatal spongiform encephalopathy characterized by rapidly progressive dementia and myoclonus. The rarity of this disease and varied initial symptoms make the early diagnosis fairly challenging. Here, we present a case initially admitted for confusion and bizarre behaviors. She had acute deterioration of mental status, akinetic mutism, and myoclonus jerks four weeks later. Cerebrospinal fluid (CSF) analysis was positive for protein 14-3-3. Brain magnetic resonance imaging (MRI) showed hyperintensities in the bilateral cortex, basal ganglia, and thalami in diffusion-weighted imaging (DWI). Electroencephalogram (EEG) showed bihemispheric periodic lateralizing epileptiform discharges. The probable diagnosis of sCJD was reached based on the clinical features, characteristic findings in her MRI, the EEG, and a positive 14-3-3 CSF assay. The literature was also reviewed for early diagnosis of sCJD.

  10. Unique inflammatory RNA profiles of microglia in Creutzfeldt-Jakob disease

    NASA Astrophysics Data System (ADS)

    Baker, Christopher A.; Manuelidis, Laura

    2003-01-01

    Previous studies in Creutzfeldt-Jakob disease (CJD) have shown that myeloid cells in the periphery as well as derivative microglial cells in the brain are infectious. Microglia can show an activated phenotype before prion protein (PrP) pathology is detectable in brain, and isolated infectious microglia contain very little PrP. To find whether a set of inflammatory genes are significantly induced or suppressed with infection, we analyzed RNA from isolated microglia with relevant cDNA arrays, and identified 30 transcripts not previously examined in any transmissible spongiform encephalopathy. This CJD expression profile contrasted with that of uninfected microglia exposed to prototypic inflammatory stimuli such as lipopolysaccharide and IFN-, as well as PrP amyloid. These findings underscore inflammatory pathways evoked by the infectious agent in brain. Transcript profiles unique for CJD microglia and other myeloid cells provide opportunities for more sensitive preclinical diagnoses of infectious and noninfectious neurodegenerative diseases.

  11. Pellagra encephalopathy as a differential diagnosis for Creutzfeldt-Jakob disease.

    PubMed

    Kapas, Istvan; Majtenyi, Katalin; Törö, Klara; Keller, Eva; Voigtländer, Till; Kovacs, Gabor G

    2012-06-01

    In the present study we evaluated cases referred as suspected Creutzfeldt-Jakob disease (CJD). Five out of 59 without prion disease showed neuropathological features of pellagra encephalopathy with widespread chromatolytic neurons (age range 40-48 years at death; one woman). These patients presented with a progressive neuropsychiatric disorder lasting for 2 to 24 months. Common symptoms included gait disorder, para- or tetraspasticity, extrapyramidal symptoms, incontinence, and myoclonus. Protein 14-3-3 in the cerebrospinal fluid was examined in a single patient and was positive, allowing the clinical classification as probable sporadic CJD. Pellagra encephalopathy may be considered as a differential diagnosis of CJD including detection of protein 14-3-3.

  12. [Phenotype and incidence of Creutzfeldt-Jakob disease in Finland in 1997-2013].

    PubMed

    Isotalo, Juuso; Gardberg, Maria; Verkkoniemi-Ahola, Auli; Paetau, Anders; Martikainen, Mika H; Korpela, Jaana; Rummukainen, Jaana; Jääskeläinen, Satu K; Parkkola, Riitta; Kaasinen, Valtteri

    2015-01-01

    The incidence of Creutzfeldt-Jakob disease (CJD) in Finland in 1974-1989 was reported to be 0.6/1 000 000. Our aim was to compare the current incidence of CJD in Finland with the earlier incidence and also study the diagnostics of the disease. Register study of the Finnish CJD cases from 1997 to 2012 and the clinical data of CJD patients within the Hospital District of Southwest Finland from 2007 to 2013. There were 119 cases. The average yearly incidence was 1.36-1.44/1 000 000. Compared with the previous study, the incidence in Finland appears to have increased. The change is propably due to increased awareness and improved diagnostic methods.

  13. Recent US Case of Variant Creutzfeldt-Jakob Disease-Global Implications.

    PubMed

    Maheshwari, Atul; Fischer, Michael; Gambetti, Pierluigi; Parker, Alicia; Ram, Aarthi; Soto, Claudio; Concha-Marambio, Luis; Cohen, Yvonne; Belay, Ermias D; Maddox, Ryan A; Mead, Simon; Goodman, Clay; Kass, Joseph S; Schonberger, Lawrence B; Hussein, Haitham M

    2015-05-01

    Variant Creutzfeldt-Jakob disease (vCJD) is a rare, fatal prion disease resulting from transmission to humans of the infectious agent of bovine spongiform encephalopathy. We describe the clinical presentation of a recent case of vCJD in the United States and provide an update on diagnostic testing. The location of this patient's exposure is less clear than those in the 3 previously reported US cases, but strong evidence indicates that exposure to contaminated beef occurred outside the United States more than a decade before illness onset. This case exemplifies the persistent risk for vCJD acquired in unsuspected geographic locations and highlights the need for continued global surveillance and awareness to prevent further dissemination of vCJD.

  14. Prion-Seeding Activity Is widely Distributed in Tissues of Sporadic Creutzfeldt-Jakob Disease Patients.

    PubMed

    Takatsuki, Hanae; Fuse, Takayuki; Nakagaki, Takehiro; Mori, Tsuyoshi; Mihara, Ban; Takao, Masaki; Iwasaki, Yasushi; Yoshida, Mari; Murayama, Shigeo; Atarashi, Ryuichiro; Nishida, Noriyuki; Satoh, Katsuya

    2016-10-01

    Human prion diseases are neurodegenerative disorders caused by abnormally folded prion proteins in the central nervous system. These proteins can be detected using the quaking-induced conversion assay. Compared with other bioassays, this assay is extremely sensitive and was used in the present study to determine prion distribution in sporadic Creutzfeldt-Jakob disease patients at autopsy. Although infectivity of the sporadic form is thought to be restricted within the central nervous system, results showed that prion-seeding activities reach 10(6)/g from a 50% seeding dose in non-neuronal tissues, suggesting that prion-seeding activity exists in non-neural organs, and we suggested that non-neural tissues of 10(6)/g SD50 did not exist the infectivity.

  15. Review. The neuropathology of kuru and variant Creutzfeldt-Jakob disease.

    PubMed

    McLean, Catriona A

    2008-11-27

    A comparison of the pathological profiles of two spongiform encephalopathies with a similar presumptive route of infection was performed. Archival kuru and recent variant Creutzfeldt-Jakob disease (vCJD) cases reveal distinct lesional differences, particularly with respect to prion protein, suggesting that the strain of agent is important in determining the phenotype. Genotype analysis of the polymorphism on codon 129 reveals (in conjunction with updated information from more kuru cases) that all three genotypes (VV, MV and MM (where M is methionine and V is valine)) are detected in kuru with some preference for MM homozygosity. The presence of valine does not therefore appear to determine peripheral selection of PrPCJD. vCJD remains restricted to date to MM homozygosity on codon 129. It remains to be determined whether this genotype is dictating a shorter incubation period.

  16. The nucleus basalis of Meynert in 20 definite cases of Creutzfeldt-Jakob disease.

    PubMed Central

    Cartier, L; Verdugo, R; Vergara, C; Galvez, S

    1989-01-01

    The population of neurons and the neuronal size in the nucleus basalis of Meynert (nbM) were studied in 20 patients with definite Creutzfeldt-Jakob disease (CJD). When compared with a normal control group, the 20 CJD brains showed a significant loss of neurons and reduction of neuronal size, mainly in the middle level of the nbM and mostly affecting the right side. Since these findings show some parallelism with the amount of cortical damage and given the scarce gliosis and spongiosis found in only six of the 20 CJD brains, we postulate that the involvement of the nbM in CJD is a retrograde abnormality secondary to the damage of the neocortex. Images PMID:2647906

  17. The Heidenhain variant of Creutzfeldt-Jakob disease and concomitant tau pathology: A case report.

    PubMed

    Ehler, Edvard; Pipka, Michael; Meleková, Alena; Mandysová, Petra; Johanidesová, Silvie; Matěj, Radoslav; Rusina, Robert

    2017-02-10

    The Heidenhain form of Creutzfeldt-Jakob disease (CJD) is a rare CJD variant with predominantly visual symptoms in the early stages. Clinical manifestations of metamorphopsia, hemianopia and Balint's syndrome correlate with the involvement of the posterior cortical regions. A 71-year old healthy and very active man was admitted because of impaired visual acuity, hemianopia, and gait disturbance progressing over one week. MRI found typical cortical hyperintensities in the occipital regions while rhythm slowing and sharp waves were seen in the occipital regions on EEG. Protein 14-3-3 was detected in the cerebrospinal fluid. Postmortem neuropathology revealed typical histopathological changes consistent with CJD. Moreover, we found deposits of phosphorylated tau protein in the limbic regions that met the criteria for primary age-related tauopathy (PART); representing an additional and interesting finding in our case.

  18. [Iatrogenic Creutzfeldt-Jakob disease. Lessons from cases secondary to extracted growth hormone in France].

    PubMed

    Billette de Villemeur, T; Pradel, A

    1994-01-01

    Thirty cases of Creutzfeldt-Jakob disease (CJD) after cadaveric growth hormone treatment have been counted by the National Reference Center for iatrogenic CJD. The clinic presentation is homogeneous, beginning by neurological troubles (diplopia, unsteady gait) evolving rapidly in few months towards a severe neurological deterioration, insanity and death. All patients were treated between January 1984 and July 1985. The risk to transmit CJD with treatments of human origin (pituitary derived treatment, blood, placentas and corneal and dura mater graft) is analyzed. The selection of donors and techniques of purification on the one hand, the rigor of the indication and the quality of the followup on the other hand, are the only guarantees to reduce the risks secondary to utilization of products of human origin.

  19. Creutzfeldt-Jakob disease with mixed transcortical aphasia: insights into echolalia.

    PubMed

    McPherson, S E; Kuratani, J D; Cummings, J L; Shih, J; Mischel, P S; Vinters, H V

    1994-01-01

    Aphasia is a common manifestation of Creutzfeldt-Jakob disease (CJD), and investigation of the linguistic disorders of CJD patients may provide insights into the neurobiological mechanisms of language and aphasia. We report an autopsy-confirmed case of CJD in which the presenting symptom was change in language abilities. The patient ultimately evidenced mixed transcortical aphasia (MTA) with echolalia. Disruption of frontal-subcortical circuits with environmental dependency accounts for the symptoms in MTA, including intact repetition and echolalia. Observation in this patient and a review of the literature suggest that frontal-subcortical circuit dysfunction may contribute to the syndrome of echolalia. This hypothesis offers an alternative explanation to "isolation" of the speech area as the cause of MTA.

  20. Cerebrospinal fluid biomarker supported diagnosis of Creutzfeldt-Jakob disease and rapid dementias: a longitudinal multicentre study over 10 years.

    PubMed

    Stoeck, Katharina; Sanchez-Juan, Pascual; Gawinecka, Joanna; Green, Alison; Ladogana, Anna; Pocchiari, Maurizio; Sanchez-Valle, Raquel; Mitrova, Eva; Sklaviadis, Theodor; Kulczycki, Jerzy; Slivarichova, Dana; Saiz, Albert; Calero, Miguel; Knight, Richard; Aguzzi, Adriano; Laplanche, Jean-Louis; Peoc'h, Katell; Schelzke, Gabi; Karch, Andre; van Duijn, Cornelia M; Zerr, Inga

    2012-10-01

    To date, cerebrospinal fluid analysis, particularly protein 14-3-3 testing, presents an important approach in the identification of Creutzfeldt-Jakob disease cases. However, one special point of criticism of 14-3-3 testing is the specificity in the differential diagnosis of rapid dementia. The constant observation of increased cerebrospinal fluid referrals in the national surveillance centres over the last years raises the concern of declining specificity due to higher number of cerebrospinal fluid tests performed in various neurological conditions. Within the framework of a European Community supported longitudinal multicentre study ('cerebrospinal fluid markers') we analysed the spectrum of rapid progressive dementia diagnoses, their potential influence on 14-3-3 specificity as well as results of other dementia markers (tau, phosphorylated tau and amyloid-β(1-42)) and evaluated the specificity of 14-3-3 in Creutzfeldt-Jakob disease diagnosis for the years 1998-2008. A total of 29 022 cerebrospinal fluid samples were analysed for 14-3-3 protein and other cerebrospinal fluid dementia markers in patients with rapid dementia and suspected Creutzfeldt-Jakob disease in the participating centres. In 10 731 patients a definite diagnosis could be obtained. Protein 14-3-3 specificity was analysed for Creutzfeldt-Jakob disease with respect to increasing cerebrospinal fluid tests per year and spectrum of differential diagnosis. Ring trials were performed to ensure the comparability between centres during the reported time period. Protein 14-3-3 test specificity remained high and stable in the diagnosis of Creutzfeldt-Jakob disease during the observed time period across centres (total specificity 92%; when compared with patients with definite diagnoses only: specificity 90%). However, test specificity varied with respect to differential diagnosis. A high 14-3-3 specificity was obtained in differentiation to other neurodegenerative diseases (95-97%) and non

  1. Human prion diseases: from Kuru to variant Creutzfeldt-Jakob disease.

    PubMed

    Sikorska, Beata; Liberski, Pawel P

    2012-01-01

    Transmissible spongiform encephalopathies (TSEs) or prion diseases are the names given to the group of fatal neurodegenerative disorders that includes kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), fatal and sporadic familial insomnia and the novel prion disease variable protease-sensitive prionopathy (PSPr) in humans. Kuru was restricted to natives of the Foré linguistic group in Papua New Guinea and spread by ritualistic endocannibalism. CJD appears as sporadic, familial (genetic or hereditary) and infectious (iatrogenic) forms. Variant CJD is a zoonotic CJD type and of major public health importance, which resulted from transmission from bovine spongiform encephalopathy (BSE) through ingestion of contaminated meat products. GSS is a slowly progressive hereditary autosomal dominant disease and the first human TSE in which a mutation in a gene encoding for prion protein (PrP) was discovered. The rarest human prion disease is fatal insomnia, which may occur, in genetic and sporadic form. More recently a novel prion disease variable protease-sensitive prionopathy (PSPr) was described in humans.TSEs are caused by a still incompletely defined infectious agent known as a "prion" which is widely regarded to be an aggregate of a misfolded isoform (PrP(Sc)) of a normal cellular glycoprotein (PrP(c)). The conversion mechanism of PrP(c) into PrP(Sc) is still not certain.

  2. A patient with a 'typical presentation' of Wernicke encephalopathy was found to have sporadic Creutzfeldt-Jakob disease.

    PubMed

    Goossens, K; van Bruchem-Visser, R L

    2017-06-01

    Creutzfeldt-Jakob disease (CJD) has a significant degree of clinical heterogeneity that is especially found in the features at onset. Here we present a patient with the sporadic form of CJD mimicking Wernicke encephalopathy. We first treated him with a high dose of thiamine; however, the vitamin B1 levels proved to be normal, which ruled out Wernicke encephalopathy. Meanwhile, his clinical condition progressively worsened and he developed a rapidly progressive cognitive disorder, mutism and myoclonus of the muscles. At this point, the diagnosis of CJD was most likely. The patient died two months after the first symptoms. Autopsy showed prion-protein depositions in several regions. Genetic analysis was negative for familial CJD. Those findings confirmed the diagnosis of 'sporadic Creutzfeldt-Jakob disease'. CJD presents in a wide range of sequences and clinical symptoms. Therefore, recognition in the early stage can be difficult.

  3. Creutzfeldt-Jakob disease in mice: persistent viremia and preferential replication of virus in low-density lymphocytes.

    PubMed Central

    Kuroda, Y; Gibbs, C J; Amyx, H L; Gajdusek, D C

    1983-01-01

    The mode of replication of the "unconventional virus" of Creutzfeldt-Jakob disease was studied in BALB/c mice infected intracerebrally. Virus was detected in the brain, spleen, lung, thymus, liver, kidney, and blood, but not in urine, at various time intervals after inoculation. The highest infectivity was present in the spleen from the second through the ninth weeks postinfection. Density gradient separation of spleen cells with colloidal silica (Percoll) revealed that the highest concentration of virus was present in blastoid cells from lower-density (1.05 to 1.07 g/ml) fractions. These results suggest that blastoid cells play an important role as the initial replication site of virus in the pathogenesis of Creutzfeldt-Jakob disease in mice. PMID:6407995

  4. Creutzfeldt-Jakob disease masked by head trauma and features of Wilson's disease.

    PubMed

    Scontrini, Alessandra; Di Bonaventura, Carlo; Fiorelli, Marco; Tiple, Dorina; Colaizzo, Elisa; Ladogana, Anna; Parchi, Piero; Pocchiari, Maurizio

    2015-04-01

    Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder typically characterized by progressive dementia associated with myoclonus, cerebellar and other focal neurological signs. Electroencephalogram, brain MRI and cerebrospinal fluid (CSF) analyses are helpful diagnostic tools, but diagnosis in patients with atypical presenting neurological signs is often difficult to make. A 55-year-old woman developed disorientation, drowsiness and focal motor signs after a traumatic brain injury due to an accidental fall. In two weeks, her symptoms worsened in spite of a brain MRI showed an improvement of traumatic lesions, but the presence of bilateral hyperintensity in the basal nuclei was suggestive of a metabolic or prion encephalopathy. The high 24-h urinary copper level and reduction of ceruloplasmin initially supported the diagnosis of Wilson's disease, but the absence of Kayser-Fleischer rings, and the positivity of 14-3-3 protein test and elevated tau concentrations in the CSF oriented toward a diagnosis of CJD. She died 5 months after the onset, and the postmortem examination of the brain revealed immunochemical features of CJD. This case exemplifies the difficulty of a timely diagnosis when rapid progressive dementia is masked by concomitant factors (i.e., head trauma) and neurological signs are associated with unclear laboratory findings.

  5. Development of Dose-Response Models of Creutzfeldt-Jakob Disease Infection in Nonhuman Primates for Assessing the Risk of Transfusion-Transmitted Variant Creutzfeldt-Jakob Disease

    PubMed Central

    Gregori, Luisa; Anderson, Steven A.; Asher, David M.

    2014-01-01

    ABSTRACT Estimates for the risk of transmitting variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion have relied largely on data from rodent experiments, but the relationship between dose (amount of infected blood) and response (vCJD infection) has never been well quantified. The goal of this study was to develop a dose-response model based on nonhuman primate data to better estimate the likelihood of transfusion-transmitted vCJD (TTvCJD) in humans. Our model used dose-response data from nonhuman primates inoculated intracerebrally (i.c.) with brain tissues of patients with sporadic and familial CJD. We analyzed the data statistically by using a beta-Poisson dose-response model. We further adjusted model parameters to account for the differences in infectivity between blood and brain tissue and in transmission efficiency between intravenous (i.v.) and i.c. routes to estimate dose-dependent TTvCJD infection. The model estimates a mean infection rate of 76% among recipients who receive one unit of whole blood collected from an infected donor near the end of the incubation period. The nonhuman primate model provides estimates that are more consistent with those derived from a risk analysis of transfused nonleukoreduced red blood cells in the United Kingdom than prior estimates based on rodent models. IMPORTANCE TTvCJD was recently identified as one of three emerging infectious diseases posing the greatest immediate threat to the safety of the blood supply. Cases of TTvCJD were reported in recipients of nonleukoreduced red blood cells and coagulation factor VIII manufactured from blood of United Kingdom donors. As the quantity of abnormal prions (the causative agent of TTvCJD) varies significantly in different blood components and products, it is necessary to quantify the dose-response relationship for a wide range of doses for the vCJD agent in transfused blood and plasma derivatives. In this paper, we suggest the first mechanistic dose-response model for

  6. Imaging of Creutzfeldt-Jakob Disease: Imaging Patterns and Their Differential Diagnosis.

    PubMed

    Fragoso, Diego Cardoso; Gonçalves Filho, Augusto Lio da Mota; Pacheco, Felipe Torres; Barros, Bernardo Rodi; Aguiar Littig, Ingrid; Nunes, Renato Hoffmann; Maia Júnior, Antônio Carlos Martins; da Rocha, Antonio J

    2017-01-01

    Diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) remains a challenge because of the large variability of the clinical scenario, especially in its early stages, which may mimic several reversible or treatable disorders. The molecular basis of prion disease, as well as its brain propagation and the pathogenesis of the illness, have become better understood in recent decades. Several reports have listed recognizable clinical features and paraclinical tests to supplement the replicable diagnostic criteria in vivo. Nevertheless, we lack specific data about the differential diagnosis of CJD at imaging, mainly regarding those disorders evolving with similar clinical features (mimicking disorders). This review provides an update on the neuroimaging patterns of sCJD, emphasizing the relevance of magnetic resonance (MR) imaging, summarizing the clinical scenario and molecular basis of the disease, and highlighting clinical, genetic, and imaging correlations in different subtypes of prion diseases. A long list of differential diagnoses produces a comprehensive pictorial review, with the aim of enabling radiologists to identify typical and atypical patterns of sCJD. This review reinforces distinguishable imaging findings and confirms diffusion-weighted imaging (DWI) features as pivotal in the diagnostic workup of sCJD, as these findings enable radiologists to reliably recognize this rare but invariably lethal disease. A probable diagnosis is justified when expected MR imaging patterns are demonstrated and CJD-mimicking disorders are confidently ruled out. (©)RSNA, 2017.

  7. Creutzfeldt-Jakob disease: updated diagnostic criteria, treatment algorithm, and the utility of brain biopsy.

    PubMed

    Manix, Marc; Kalakoti, Piyush; Henry, Miriam; Thakur, Jai; Menger, Richard; Guthikonda, Bharat; Nanda, Anil

    2015-11-01

    Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative condition with a rapid disease course and a mortality rate of 100%. Several forms of the disease have been described, and the most common is the sporadic type. The most challenging aspect of this disease is its diagnosis-the gold standard for definitive diagnosis is considered to be histopathological confirmation-but newer tests are providing means for an antemortem diagnosis in ways less invasive than brain biopsy. Imaging studies, electroencephalography, and biomarkers are used in conjunction with the clinical picture to try to make the diagnosis of CJD without brain tissue samples, and all of these are reviewed in this article. The current diagnostic criteria are limited; test sensitivity and specificity varies with the genetics of the disease as well as the clinical stage. Physicians may be unsure of all diagnostic testing available, and may order outdated tests or prematurely request a brain biopsy when the diagnostic workup is incomplete. The authors review CJD, discuss the role of brain biopsy in this patient population, provide a diagnostic pathway for the patient presenting with rapidly progressive dementia, and propose newer diagnostic criteria.

  8. The prion protein preference of sporadic Creutzfeldt-Jakob disease subtypes.

    PubMed

    Klemm, Helen M J; Welton, Jeremy M; Masters, Colin L; Klug, Genevieve M; Boyd, Alison; Hill, Andrew F; Collins, Steven J; Lawson, Victoria A

    2012-10-19

    Sporadic Creutzfeldt-Jakob disease (CJD) is the most prevalent manifestation of the transmissible spongiform encephalopathies or prion diseases affecting humans. The disease encompasses a spectrum of clinical phenotypes that have been correlated with molecular subtypes that are characterized by the molecular mass of the protease-resistant fragment of the disease-related conformation of the prion protein and a polymorphism at codon 129 of the gene encoding the prion protein. A cell-free assay of prion protein misfolding was used to investigate the ability of these sporadic CJD molecular subtypes to propagate using brain-derived sources of the cellular prion protein (PrP(C)). This study confirmed the presence of three distinct sporadic CJD molecular subtypes with PrP(C) substrate requirements that reflected their codon 129 associations in vivo. However, the ability of a sporadic CJD molecular subtype to use a specific PrP(C) substrate was not determined solely by codon 129 as the efficiency of prion propagation was also influenced by the composition of the brain tissue from which the PrP(C) substrate was sourced, thus indicating that nuances in PrP(C) or additional factors may determine sporadic CJD subtype. The results of this study will aid in the design of diagnostic assays that can detect prion disease across the diversity of sporadic CJD subtypes.

  9. A Common BACE1 Polymorphism Is a Risk Factor for Sporadic Creutzfeldt-Jakob Disease

    PubMed Central

    Calero, Olga; Bullido, María J.; Clarimón, Jordi; Frank-García, Ana; Martínez-Martín, Pablo; Lleó, Alberto; Rey, María Jesús; Sastre, Isabel; Rábano, Alberto; de Pedro-Cuesta, Jesús; Ferrer, Isidro; Calero, Miguel

    2012-01-01

    The β site APP cleaving enzyme 1 (BACE1) is the rate-limiting β-secretase enzyme in the amyloidogenic processing of APP and Aβ formation, and therefore it has a prominent role in Alzheimer’s disease (AD) pathology. Recent evidence suggests that the prion protein (PrP) interacts directly with BACE1 regulating its β-secretase activity. Moreover, PrP has been proposed as the cellular receptor involved in the impairment of synaptic plasticity and toxicity caused by Aβ oligomers. Provided that common pathophysiologic mechanisms are shared by Alzheimer’s and Creutzfeldt-Jakob (CJD) diseases, we investigated for the first time to the best of our knowledge a possible association of a common synonymous BACE1 polymorphism (rs638405) with sporadic CJD (sCJD). Our results indicate that BACE1 C-allele is associated with an increased risk for developing sCJD, mainly in PRNP M129M homozygous subjects with early onset. These results extend the very short list of genes (other than PRNP) involved in the development of human prion diseases; and support the notion that similar to AD, in sCJD several loci may contribute with modest overall effects to disease risk. These findings underscore the interplay in both pathologies of APP, Aβ oligomers, ApoE, PrP and BACE1, and suggest that aging and perhaps vascular risk factors may modulate disease pathologies in part through these key players. PMID:22952813

  10. Assessing Prion Infectivity of Human Urine in Sporadic Creutzfeldt-Jakob Disease

    PubMed Central

    Notari, Silvio; Qing, Liuting; Pocchiari, Maurizio; Dagdanova, Ayuna; Hatcher, Kristin; Dogterom, Arend; Groisman, Jose F.; Lumholtz, Ib Bo; Puopolo, Maria; Lasmezas, Corinne; Chen, Shu G.; Kong, Qingzhong

    2012-01-01

    Prion diseases are neurodegenerative conditions associated with a misfolded and infectious protein, scrapie prion protein (PrPSc). PrPSc propagate prion diseases within and between species and thus pose risks to public health. Prion infectivity or PrPSc presence has been demonstrated in urine of experimentally infected animals, but there are no recent studies of urine from patients with Creutzfeldt-Jakob disease (CJD). We performed bioassays in transgenic mice expressing human PrP to assess prion infectivity in urine from patients affected by a common subtype of sporadic CJD, sCJDMM1. We tested raw urine and 100-fold concentrated and dialyzed urine and assessed the sensitivity of the bioassay along with the effect of concentration and dialysis on prion infectivity. Intracerebral inoculation of transgenic mice with urine from 3 sCJDMM1 patients failed to demonstrate prion disease transmission, indicating that prion infectivity in urine from sCJDMM1 patients is either not present or is <0.38 infectious units/mL. PMID:22260924

  11. A transmissible Creutzfeldt-Jakob disease-like agent is prevalent in the human population.

    PubMed Central

    Manuelidis, E E; Manuelidis, L

    1993-01-01

    The etiology of most human dementias is unknown. Creutzfeldt-Jakob disease (CJD), a relatively uncommon human dementia, is caused by a transmissible virus-like agent. Molecular markers that are specific for the agent have not yet been defined. However, the infectious disease can be transmitted to rodents from both brain and infected buffy coat (blood) samples. To determine whether human CJD infections are more widespread than is apparent from the low incidence of neurological disease, we attempted to transmit CJD from buffy coat samples of 30 healthy volunteers who had no family history of dementing illness. Primary transmissions from 26 of 30 individuals produced CJD-like spongiform changes in the brains of recipient hamsters at 200-500 days postinoculation. This positive evidence of viremia was found for individuals in all age groups (20-30, 40-50, and 61-71 years old), whereas 12 negatively scored brain samples failed to produce similar changes in hamsters observed for > 900 days in the same setting. We suggest that a CJD agent endemically infects humans but only infrequently produces an infectious dementia. Disease expression is likely to be influenced by several host factors in combination with viral variants that have altered neurovirulence. Images Fig. 1 PMID:8356076

  12. Factors influencing the survival period in Japanese patients with sporadic Creutzfeldt-Jakob disease.

    PubMed

    Iwasaki, Yasushi; Akagi, Akio; Mimuro, Maya; Kitamoto, Tetsuyuki; Yoshida, Mari

    2015-10-15

    Although Japanese cases of sporadic Creutzfeldt-Jakob disease (sCJD) generally involve longer survival periods compared to those from other countries, details regarding the factors influencing survival are unclear. To determine the influence of certain factors on survival, we retrospectively assessed 51 Japanese MM1-type sCJD patients with respect to background, clinical course, and disease management. No significant differences were found between men and women, tracheotomy and nontracheotomy patients, or patients treated in public and other types of hospitals. Although the survival period of tube-fed patients was significantly longer than that of patients who were not tube fed, survival of patients fed via a nasal tube did not differ significantly from that of gastrostomy-fed patients. The proportion of tube-fed patients was 68.6% (35/51). Disease duration was not significantly associated with age or year of onset. However, it was associated with time from onset to first recognition of myoclonus, first recognition of periodic sharp-wave complexes on electroencephalogram, and progression to the akinetic mutism state. Mechanical ventilation was not performed for any patient. Because the total disease duration increased in cases with a slowly progressive clinical course as a natural outcome, we concluded that the most crucial factor contributing to the prolonged survival of Japanese sCJD patients was tube feeding once the akinetic mutism state had been reached.

  13. A Corticobasal Syndrome Variant of Familial Creutzfeldt-Jakob Disease with Stroke-Like Onset

    PubMed Central

    2016-01-01

    Creutzfeldt-Jakob disease (CJD) is an untreatable rare human prion disease characterized by rapidly progressive dementia along with various neurological features, including myoclonus and sometimes other movement disorders. The clinical course is typically insidious and rapid, leading to an early death. In general, the most common form is sporadic CJD; however, Slovakia is typical for a high percentage of genetic cases. We present an unusual case report of a 65-year-old man with a sudden, stroke-like onset of motor aphasia with right-sided levodopa unresponsive parkinsonism, alien hand, and other characteristic features of corticobasal syndrome (CBS), with rapid deterioration and death on the 32nd day of the disease. Various neurodegenerative disorders are manifested with CBS as a clinical phenotype, including corticobasal degeneration (CBD), progressive supranuclear palsy, Alzheimer's disease, and CJD. In our patient, mutation E200K and M129M polymorphism of the PRNP gene and typical immunohistochemical findings pointed to a diagnosis of CJD. The patient's mother died of CJD many years ago. Several CBS-CJD cases were described, but the atypical stroke-like onset of CBS-CJD, an extremely rare presentation of CJD, makes our case unique worldwide. PMID:27803826

  14. Codon 219 polymorphism of PRNP in healthy caucasians and Creutzfeldt-Jakob disease patients

    SciTech Connect

    Petraroli, R.; Pocchiari, M.

    1996-04-01

    A number of point and insert mutations of the PrP gene (PRNP) have been linked to familial Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker disease (GSS). Moreover, the methionine/valine homozygosity at the polymorphic codon 129 of PRNP may cause a predisposition to sporadic and iatrogenic CJD or may control the age at onset of familial cases carrying either the 144-bp insertion or codon 178, codon 198, and codon 210 pathogenic mutations in PRNP. In addition, the association of methionine or valine at codon 129 and the point mutation at codon 178 on the same allele seem to play an important role in determining either fatal familial insomnia or CJD. However, it is noteworthy that a relationship between codon 129 polymorphism and accelerated pathogenesis (early age at onset or shorter duration of the disease) has not been seen in familial CJD patients with codon 200 mutation or in GSS patients with codon 102 mutation, arguing that other, as yet unidentified, gene products or environmental factors, or both, may influence the clinical expression of these diseases. 17 refs.

  15. Cerebrospinal fluid tau levels are a marker for molecular subtype in sporadic Creutzfeldt-Jakob disease.

    PubMed

    Karch, André; Hermann, Peter; Ponto, Claudia; Schmitz, Matthias; Arora, Amandeep; Zafar, Saima; Llorens, Franc; Müller-Heine, Annika; Zerr, Inga

    2015-05-01

    The molecular subtype of sporadic Creutzfeldt-Jakob disease (sCJD) is an important prognostic marker for patient survival. However, subtype determination is not possible during lifetime. Because the rate of disease progression is associated with the molecular subtype, this study aimed at investigating if total tau, a marker of neuronal death, allows premortem diagnosis of molecular subtype when codon 129 genotype is known. Two hundred ninety-six sCJD patients were tested for their cerebrospinal fluid total tau level at the time of diagnosis and were investigated for their sCJD subtype postmortem. There was a significant association between tau levels and the prion protein type in patients with codon 129 MM (p < 0.001), MV (p = 0.004), and VV (p = 0.001) genotype. Receiver operating characteristic analyses showed values of area under the curve of 0.76-0.80 for the different genotypes indicating a good diagnostic validity of the test. Total tau can be used as a diagnostic test for the assessment of prion protein type when codon 129 genotype is known. It provides valuable information for physicians and next of kin about the further course of disease.

  16. Neurofilaments in blood and CSF for diagnosis and prediction of onset in Creutzfeldt-Jakob disease

    PubMed Central

    Steinacker, Petra; Blennow, Kaj; Halbgebauer, Steffen; Shi, Song; Ruf, Viktoria; Oeckl, Patrick; Giese, Armin; Kuhle, Jens; Slivarichova, Dana; Zetterberg, Henrik; Otto, Markus

    2016-01-01

    While cerebrospinal fluid (CSF) biomarkers for Creutzfeldt-Jakob disease (CJD) are established and partly included in the diagnostic criteria, no blood biomarkers are available. Here, we assessed the utility of serum neurofilament light chain (NF-L) and tau protein in comparison to CSF markers (NF-L and phosphorylated NF heavy chain (pNF-H), tau, S100B, 14-3-3) and prion conversion assay (real-time quaking induced conversion (RT-QuIC)) for sporadic and genetic CJD. Importantly, a Gerstmann-Sträussler-Scheinker mutation carrier in the asymptomatic phase and at disease onset was included as well. Both NF-L and tau were markedly increased in CJD serum, reaching similar or even better performance as in CSF (sensitivity and specificity for serum NF-L 100% and 85.5%, and for serum tau 84.6% and 96.2%, respectively). Serum S100B showed high sensitivity as well (84.2%), but lower specificity (63%). CSF neurofilaments were increased before symptom onset, while prion seeding assay was negative. Just before a clinical diagnosis could be made, all CSF markers and NF-L in the serum were increased and CSF prion conversion assay was positive. The data suggest that neurofilaments are sensitive and specific blood markers for the diagnosis of genetic and sporadic CJD and might represent promising tools to predict disease onset. PMID:27929120

  17. Regulation of human cerebrospinal fluid malate dehydrogenase 1 in sporadic Creutzfeldt-Jakob disease patients

    PubMed Central

    Schmitz, Matthias; Llorens, Franc; Pracht, Alexander; Thom, Tobias; Correia, Ângela; Zafar, Saima; Ferrer, Isidre; Zerr, Inga

    2016-01-01

    The identification of reliable diagnostic biomarkers in differential diagnosis of neurodegenerative diseases is an ongoing topic. A previous two-dimensional proteomic study on cerebrospinal fluid (CSF) revealed an elevated level of an enzyme, mitochondrial malate dehydrogenase 1 (MDH1), in sporadic Creutzfeldt-Jakob disease (sCJD) patients. Here, we could demonstrate the expression of MDH1 in neurons as well as in the neuropil. Its levels are lower in sCJD brains than in control brains. An examination of CSF-MDH1 in sCJD patients by ELISA revealed a significant elevation of CSF-MDH1 levels in sCJD patients (independently from the PRNP codon 129 MV genotype or the prion protein scrapie (PrPSc) type) in comparison to controls. In combination with total tau (tau), CSF-MDH1 detection exhibited a high diagnostic accuracy for sCJD diagnosis with a sensitivity of 97.5% and a specificity of 95.6%. A correlation study of MDH1 level in CSF with other neurodegenerative marker proteins revealed a significant positive correlation between MDH1 concentration with tau, 14-3-3 and neuron specific enolase level. In conclusion, our study indicated the potential of MDH1 in combination with tau as an additional biomarker in sCJD improving diagnostic accuracy of tau markedly. PMID:27852982

  18. Variant Creutzfeldt-Jakob Disease With Extremely Low Lymphoreticular Deposition of Prion Protein

    PubMed Central

    Mead, Simon; Wadsworth, Jonathan D. F.; Porter, Marie-Claire; Linehan, Jacqueline M.; Pietkiewicz, Wojciech; Jackson, Graham S.; Brandner, Sebastian; Collinge, John

    2014-01-01

    IMPORTANCE Human transmission of bovine spongiform encephalopathy causes the fatal neurodegenerative condition variant Creutzfeldt-Jakob disease (vCJD) and, based on recent human prevalence studies, significant subclinical prion infection of the UK population. To date, all clinical cases have been fatal, totaling 228 mostly young adults residing in the United Kingdom. OBSERVATIONS Here we describe the investigation and case history of a patient recently diagnosed as having vCJD in the United Kingdom. Although his presentation, imaging findings, cerebrospinal fluid investigation results, and clinical progression were typical of other cases, tonsillar biopsy and subsequent examination of multiple tissues at autopsy showed minimal deposition of disease-associated prion protein in peripheral lymphoreticular tissue. The result of a blood test for vCJD, the Direct Detection Assay for vCJD, was negative. CONCLUSIONS AND RELEVANCE These findings suggest that some patients with vCJD have very low peripheral prion colonization and therefore may not have detectable prion deposition in diagnostic tonsillar biopsy or markers of prion infection in blood. These results have implications for accurate interpretation of diagnostic tests and prevalence studies based on lymphoreticular tissue or blood. PMID:24445428

  19. Three sporadic cases of Creutzfeldt-Jakob disease in China and their clinical analysis.

    PubMed

    Wang, Xingbang; Li, Na; Liu, Aifen; Ma, Lin; Shan, Peiyan; Jiang, Wenjing; Zhang, Qun

    2017-09-01

    The present study described the characteristics of three cases of Creutzfeldt-Jakob disease (CJD) in China and analyzed their clinical presentations. The clinical information of the three cases was collected and analyzed. Blood and cerebrospinal fluid (CSF) specimens of the patients were collected for detection of the prion protein (PRNP) gene and 14-3-3 protein levels. Dynamic changes of electroencephalograms (EEGs) and brain magnetic resonance images (MRIs) were also observed. All the three cases were sporadic CJD cases. They presented with symptoms including hyposthenia, progressive memory loss, truncal and limb ataxia, dysarthria, lowered vision acuity, bucking, language disorders, myoclonia and akinetic mutism state. One of the three cases was associated with a prolonged duration of >6 years. The EEG of two cases showed slow biphasic waves. The diffusion-weighted MRI sequence revealed abnormal hyperintensity and bilateral ribboning in the cortex. Two patients tested positive for the 14-3-3 protein in the CSF. All patients were of methionine homozygosity at codon 129 in the gene encoding PRNP protein and one patient had a mutation. The CJD cases showed differences in terms of symptoms and disease duration. Subacute onset was common and with attentive nursing and supportive treatments, one of the patients had a prolonged survival time of >6 years.

  20. Creutzfeldt-Jakob disease (CJD) in a case of suspected chronic heavy metal poisoning.

    PubMed

    Oehmichen, M; Schulz-Schaeffer, W; Kretzschmar, H; Theuerkauf, I; Gerling, I; Windl, O; Meissner, C

    2001-05-01

    We describe a patient who died of suspected heavy metal poisoning after a nine-month history of rapidly worsening dementia. Autopsy at a forensic-pathological institute established the postmortem diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) based on demonstration of the proteinase-resistant prion protein (PrPsSc) in Western-Blot on native brain tissue. Microscopic examination of the macroscopically largely inconspicuous brain revealed marked spongiform changes in the gray matter--mainly affecting the cerebral cortex, nucleus caudatus, and putamen--with confluent vacuoles. Patchy or perivacuolar deposits of PrPSc were found as well as granular PrPsc deposits. The cerebellum contained focal PrPsc deposits. There was an astrogliosis in the white matter and a proliferation of microglia in the gray matter with a simultaneous clear reduction in neuronal elements. The differential diagnosis is discussed, as is the potential risk to those performing autopsy on forensic cases with a clinical picture of rapidly progressing dementia, especially in cases where a prion disease is not initially suspected.

  1. Rapid detection of Creutzfeldt-Jakob disease and scrapie prion proteins.

    PubMed

    Serban, D; Taraboulos, A; DeArmond, S J; Prusiner, S B

    1990-01-01

    Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler syndrome (GSS) of humans as well as scrapie of animals are caused by prions. The scrapie prion protein isoform (PrPSc) is the only macromolecule identified to date which is a component of the infectious prion particle. PrPSc is converted to PrP 27-30 by limited proteolysis while the cellular isoform, designated PrPC, is completely digested under the same conditions. ELISA studies demonstrated that native PrP 27-30 bound to plastic surfaces resisted proteolysis and exhibited little or no immunoreactivity but after denaturation with guanidinium thiocyanate (GdnSCN), immunoreactivity was greatly enhanced. PrPSc bound to nitrocellulose also exhibited enhanced immunoreactivity after denaturation. PrPSc was readily detected in brain extracts from scrapie-infected hamsters, mice, and sheep by dot-blot immunoassays using limited proteolysis followed by GdnSCN denaturation. The high sensitivity and specificity of the immunoassay allowed detection of regional differences in PrPSc in sheep brain. CJD prion protein isoform (PrPCJD) was also detected in the brains of all 10 patients tested with neuropathologically confirmed CJD and in 1 patient with GSS. Enhanced immunoreactivity of PrPSc or PrPCJD after denaturation cannot only be used for immunodiagnosis of prion diseases but may also form the basis of new assays in experimental studies directed at the chemical structure of the prion particle.

  2. Management of neurosurgical instruments and patients exposed to Creutzfeldt-Jakob disease.

    PubMed

    Belay, Ermias D; Blase, Jennifer; Sehulster, Lynne M; Maddox, Ryan A; Schonberger, Lawrence B

    2013-12-01

    To summarize the approaches used to manage exposure of patients to inadequately sterilized neurosurgical instruments contaminated as a result of Creutzfeldt-Jakob disease (CJD). Information on past CJD exposure incidents reported to the Centers for Disease Control and Prevention (CDC) was aggregated and summarized. In addition, inactivation studies were reviewed, and data from selected publications were provided for reference. Nineteen incidents of patient exposure to potentially CJD-contaminated instruments were reported to the CDC, including 17 that involved intracranial procedures and 2 that involved ophthalmologic procedures. In more than 50% of incidents, the neurosurgical procedures were performed for diagnostic work up of the index patients. At least 12 of the hospitals had multiple neurosurgical sets, and the CJD-contaminated instruments could not be identified in 11 of 19 hospitals. In 12 of 15 hospitals with neurosurgical incidents, a decision was made to notify patients of their potential exposure. Neurosurgical instruments used for treatment of patients with suspected or diagnosed CJD or patients whose diagnosis is unclear should be promptly identified and sterilized using recommended CJD decontamination protocols. Inability to trace instruments complicates appropriate management of exposure incidents. The feasibility of instituting instrument tracking procedures should be considered.

  3. Positive 14-3-3 and tau proteins in a sporadic Creutzfeldt-Jakob disease case and a brief perspective of prion diseases in Colombia.

    PubMed

    Escandón-Vargas, Kevin; Zorrilla-Vaca, Andrés; Corral-Prado, Raúl Heli

    2016-02-24

    Prion diseases are rare neurodegenerative disorders occurring worldwide and affecting both humans and animals. Herein, we present the case of a patient diagnosed with definite sporadic Creutzfeldt-Jakob disease in Cali, Colombia. Besides neurological examination, 14-3-3 and tau proteins were valuable tools supporting the diagnosis. We also present a brief perspective of the prion diseases reported in Colombia to date. Although the incidence of prion diseases is unknown in Colombia, our literature review revealed that one case of scrapie in 1981 and 29 human sporadic cases of Creutzfeldt-Jakob disease have been documented and published in our country.

  4. The sequential development of abnormal prion protein accumulation in mice with Creutzfeldt-Jakob disease.

    PubMed Central

    Muramoto, T.; Kitamoto, T.; Tateishi, J.; Goto, I.

    1992-01-01

    The distribution and sequential development of prion protein (PrP) accumulation in the central nervous system (CNS) and non-neuronal organs of mice infected with Creutzfeldt-Jakob disease (CJD) were investigated immunohistochemically using a new pretreatment method that greatly enhanced the immunoreactivity of PrP. Prion protein accumulation in the CNS was first detected at 30 days after inoculation and then developed near the inoculation site or periventricular area, and later spread to the whole cerebrum and then to the pons. Its staining took some characteristic forms. Among non-neuronal organs, PrP accumulated in the follicular dendritic cells (FDCs) in spleen, lymph node, Peyer's patch, and thymus. FDCs staining appeared in spleen, lymph node, and Peyer's patch at 21 or 30 days after inoculation, and in thymus at 90 days. Germinal centers developed in the thymus of some CJD-infected mice. No PrP staining was detected in any examined organs of age-matched control mice. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:1376559

  5. The French surveillance network of Creutzfeldt-Jakob disease. Epidemiological data in France and worldwide.

    PubMed

    Brandel, J-P; Peckeu, L; Haïk, S

    2013-09-01

    France, involved for a long time in the epidemiological surveillance of transmissible spongiform encephalopathy (TSE), created a national network of surveillance in 1991, because of the description of the first cases of Creutzfeldt-Jakob disease (CJD) linked to a treatment by growth hormone of human origin and the observation of cases of cats infected with the agent of the bovine spongiform encephalopathy in the United Kingdom (UK). The French surveillance network is integrated into the European network of surveillance since its creation in 1993. As in other countries, sporadic CJD is the most frequent form of TSE in France with an annual mortality rate of 1.44 per million. Genetic forms are most often associated with a mutation at codon 200. Among the cases of iatrogenic CJD, 13 cases of CJD after duramater grafts were observed and 119 related to treatment with growth hormone. France is the country worst affected in Europe and the world by this latter form, before the USA and UK. Since 1996, 27 cases of variant of CJD (vCJD) has been observed, making France the second country in the world most affected after the UK. No cases of transfusion-associated vCJD have been observed. Copyright © 2013. Published by Elsevier SAS.

  6. [A case of Creutzfeldt-Jakob disease presenting with arm levitation as an initial symptom].

    PubMed

    Kamogawa, Kenji; Ninomiya, Satoko; Okuda, Shinya; Matsumoto, Yushi; Tomita, Hitomi; Okamoto, Kensho; Okuda, Bungo

    2014-01-01

    A 74-year-old, right handed man, developed insidiously with levitation and clumsiness of the right upper limb. His right arm tended to levitate spontaneously, when he was examined. He could put the elevated arm down on command, while the arm resumed to antigravity posture when his attention was diverted. His right arm also exhibited unwilled elevation when performing complex finger movements on the right side. He had a feeling of strangeness of the elevated limb, especially with the eyes closed. In addition to asymmetric limb-kinetic apraxia, combined sensations such as stereognosis were disturbed on the right side. Brain MRI showed high signal lesions predominantly in the left cerebral cortices and basal ganglia. SPECT with (123)I-IMP revealed asymmetric hypoperfusion, predominantly in the left medial frontal and parietal regions. Two months after the onset, levitation of the arm gradually disappeared, with the development of rapidly progressive dementia, frontal signs, dystonia and generalized myoclonus. The diagnosis of Creutzfeldt-Jakob disease (CJD) was made based on the clinical features and cerebrospinal fluid biomarkers. The early manifestation of the patient mimicked corticobasal degeneration which presents with arm levitation or alien hand syndrome. It is suggested that CJD can represent involuntary movements with higher brain dysfunction resembling corticobasal degeneration at the early stage of the illness. Although the underlying mechanism of arm levitation is still unknown, frontal disinhibition and parietal cortical sensory disturbance may contribute to the development of involuntary arm levitation in our patient.

  7. Comparison Between Sporadic and Misdiagnosed Sporadic Creutzfeldt-Jakob Disease: A Report of Two Cases.

    PubMed

    Zhao, Xiongfei; Yu, Yingxin; Zhao, Zhiru; Xu, Jiaping

    2015-06-01

    Definite accurate diagnosis for Creutzfeldt-Jakob disease (CJD) depends on neuropathologic examination of brain biopsy or autopsy. However, transmissible nature makes the invasive examination dangerous. This study was set to determine that the clinical features are for the diagnosis of CJD through a comparison study. We compared clinical features of two cases with initial diagnosis of sporadic CJD. One case was finally diagnosed as definite sporadic CJD. According to World Health Organization diagnosis criteria, the other one, which had been diagnosed as probable sporadic CJD, was confirmed as limbic encephalitis after long-term follow-up. Compared with the case of definite sporadic CJD, the misdiagnosed case did not present typical electroencephalogram (EEG) and diffusion-weighted in magnetic resonance images (DWI) of CJD. However, cerebrospinal fluid in the misdiagnosed patient showed 14-3-3 protein positivity. The patient conditions improved after treatment. Through this case comparison, we conclude that EEG and DWI are necessary for accurate diagnosis of sporadic CJD. Further, long-term follow-up is crucial to diagnosis and treatment of CJD.

  8. The epidemics of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: current status and future prospects.

    PubMed Central

    Smith, Peter G.

    2003-01-01

    The large epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom has been in decline since 1992, but has spread to other countries. The extensive control measures that have been put in place across the European Union and also in Switzerland should have brought the transmission of BSE under control in these countries, provided that the measures were properly enforced. Postmortem tests on brain tissue enable infected animals to be detected during the late stages of the incubation period, but tests that can be performed on live animals (including humans) and that will detect infections early are urgently needed. The number of infected animals currently entering the food chain is probably small, and the controls placed on bovine tissues in the European Union and Switzerland should ensure that any risks to human health are small and diminishing. Vigilance is required in all countries, especially in those in which there has been within-species recycling of ruminant feed. Fewer than 150 people, globally, have been diagnosed with variant Creutzfeldt-Jakob disease (vCJD), but there are many uncertainties about the future course of the epidemic because of the long and variable incubation period. Better control measures are necessary to guard against the possibility of iatrogenic transmission through blood transfusion or contaminated surgical instruments. These measures will required sensitive and specific, diagnostic tests and improved decontamination methods. PMID:12751420

  9. Creutzfeldt-jakob, Parkinson, lewy body dementia and Alzheimer diseases: from diagnosis to therapy.

    PubMed

    Dupiereux, Ingrid; Zorzi, Willy; Quadrio, Isabelle; Perret-Liaudet, Armand; Kovacs, Gabor G; Heinen, Ernst; Elmoualij, Benaïssa

    2009-03-01

    Depositions of proteins in form of amyloid and non-amyloid plaques are common pathogenic signs of more than 20 degenerative diseases affecting the central nervous system or a variety of peripheral tissues. Among the neuropathological conditions, Alzheimer's, Parkinson's and the prion diseases, such as Creutzfeldt-Jakob disease (CJD), present ambiguities as regarding their differential diagnosis. At present, their diagnosis must be confirmed by post-mortem examination of the brain. Currently the ante-mortem diagnosis is still based on the integration of multiple data (clinical, paraclinical and biological analyses) because no unique marker exists for such diseases. The detection of specific biomarkers would be useful to develop a differential diagnostic, distinguishing not only different neurodegenerative diseases but also the disease from the non-pathological effects of aging. Several neurodegenerative biomarkers are present at very low levels during the early stages of the disease development and their ultra-low detection is needed for early diagnosis, which should permit more effective therapeutic interventions, before the disease concerned can progress to a stage where considerable damage to the brain has already occurred. In the case of prion diseases, there are concerns regarding not only patient care, but the wider community too, with regard to the risk of transmission of prions, especially during blood transfusion, for which, four cases of variant CJD infection associated with transfusion of non-leukocyte-depleted blood components have been confirmed. Therefore the development of techniques with high sensitivity and specificity represent the major challenge in the field of the protein misfolding diseases. In this paper we review the current analytical and/or biochemical diagnostic technologies used mainly in prion, but also in Alzheimer and Parkinson diseases and emphasizing work on the protein detection as a surrogates and specific biomarker in the body

  10. Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies.

    PubMed

    López González, Irene; Garcia-Esparcia, Paula; Llorens, Franc; Ferrer, Isidre

    2016-02-04

    Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer's disease (AD) and sporadic Parkinson's disease (sPD). Gene expression studies of cytokines and mediators of the immune response have been made in post-mortem human brain samples in AD, sPD, sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2, Pick's disease (PiD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration linked to mutation P301L in MAPT Frontotemporal lobar degeneration-tau (FTLD-tau). The studies have disclosed variable gene regulation which is: (1) disease-dependent in the frontal cortex area 8 in AD, sPD, sCJD MM1 and VV2, PiD, PSP and FTLD-tau; (2) region-dependent as seen when comparing the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 (FC) in AD; the substantia nigra, putamen, FC, and angular gyrus in PD, as well as the FC and cerebellum in sCJD; (3) genotype-dependent as seen considering sCJD MM1 and VV2; and (4) stage-dependent as seen in AD at different stages of disease progression. These observations show that regulation of inflammation is much more complicated and diverse than currently understood, and that new therapeutic approaches must be designed in order to selectively act on specific targets in particular diseases and at different time points of disease progression.

  11. Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies

    PubMed Central

    López González, Irene; Garcia-Esparcia, Paula; Llorens, Franc; Ferrer, Isidre

    2016-01-01

    Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer’s disease (AD) and sporadic Parkinson’s disease (sPD). Gene expression studies of cytokines and mediators of the immune response have been made in post-mortem human brain samples in AD, sPD, sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2, Pick’s disease (PiD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration linked to mutation P301L in MAPT Frontotemporal lobar degeneration-tau (FTLD-tau). The studies have disclosed variable gene regulation which is: (1) disease-dependent in the frontal cortex area 8 in AD, sPD, sCJD MM1 and VV2, PiD, PSP and FTLD-tau; (2) region-dependent as seen when comparing the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 (FC) in AD; the substantia nigra, putamen, FC, and angular gyrus in PD, as well as the FC and cerebellum in sCJD; (3) genotype-dependent as seen considering sCJD MM1 and VV2; and (4) stage-dependent as seen in AD at different stages of disease progression. These observations show that regulation of inflammation is much more complicated and diverse than currently understood, and that new therapeutic approaches must be designed in order to selectively act on specific targets in particular diseases and at different time points of disease progression. PMID:26861289

  12. Role of the biomarkers for the diagnosis of Creutzfeldt-Jakob disease

    PubMed Central

    Dulamea, A; Solomon, E

    2016-01-01

    Objective: Sporadic Creutzfeldt-Jakob disease (CJD) is a human prion disease, rapidly progressive and fatal, characterized by spongiform encephalopathy. The characteristic triad of signs - rapidly progressive dementia, myoclonus and periodic sharp wave complexes (PSWC) on electroencephalography (EEG) - usually appear in the late stages of the disease. The clinical diagnosis of CJD ante-mortem involves the exclusion of the rapidly progressive non-prionic dementias, the definitive diagnosis requiring brain tissue confirmation. Authors evaluated the methods of clinical diagnosis for sporadic CJD. Methods: This study retrospectively reviewed the medical records of patients diagnosed with probable sporadic CJD, based on brain magnetic resonance imaging (MRI), EEG, cerebrospinal fluid (CSF) analysis and extensive laboratory work-up. Results: Four patients with a mean age of 67 years were included in our study. The mean duration from diagnosis until death was of 3.2 weeks. The clinical features of the disease at onset were atypical. In the final stage of the disease, all patients presented rapidly progressive dementia and myoclonus. High levels of 14-3-3 protein and tau protein and normal levels of amyloid β1-42 were found at CSF analysis, in all patients. PSWC on EEG were present in 3 out of 4 patients at different moments of the disease. MRI showed hyperintense lesions in brain cortex, caudate nucleus, and putamen on T2, FLAIR, and DWI. Conclusion: CJD may present various clinical features and, since brain biopsy is usually difficult to perform, a combination of biomarkers is useful in order to establish the diagnosis in the early phase of the disease. PMID:27453757

  13. The Distribution of Prion Protein Allotypes Differs Between Sporadic and Iatrogenic Creutzfeldt-Jakob Disease Patients

    PubMed Central

    Moore, Roger A.; Head, Mark W.; Ironside, James W.; Ritchie, Diane L.; Zanusso, Gianluigi; Pyo Choi, Young; Priola, Suzette A.

    2016-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent of the human prion diseases, which are fatal and transmissible neurodegenerative diseases caused by the infectious prion protein (PrPSc). The origin of sCJD is unknown, although the initiating event is thought to be the stochastic misfolding of endogenous prion protein (PrPC) into infectious PrPSc. By contrast, human growth hormone-associated cases of iatrogenic CJD (iCJD) in the United Kingdom (UK) are associated with exposure to an exogenous source of PrPSc. In both forms of CJD, heterozygosity at residue 129 for methionine (M) or valine (V) in the prion protein gene may affect disease phenotype, onset and progression. However, the relative contribution of each PrPC allotype to PrPSc in heterozygous cases of CJD is unknown. Using mass spectrometry, we determined that the relative abundance of PrPSc with M or V at residue 129 in brain specimens from MV cases of sCJD was highly variable. This result is consistent with PrPC containing an M or V at residue 129 having a similar propensity to misfold into PrPSc thus causing sCJD. By contrast, PrPSc with V at residue 129 predominated in the majority of the UK human growth hormone associated iCJD cases, consistent with exposure to infectious PrPSc containing V at residue 129. In both types of CJD, the PrPSc allotype ratio had no correlation with CJD type, age at clinical onset, or disease duration. Therefore, factors other than PrPSc allotype abundance must influence the clinical progression and phenotype of heterozygous cases of CJD. PMID:26840342

  14. The Distribution of Prion Protein Allotypes Differs Between Sporadic and Iatrogenic Creutzfeldt-Jakob Disease Patients.

    PubMed

    Moore, Roger A; Head, Mark W; Ironside, James W; Ritchie, Diane L; Zanusso, Gianluigi; Choi, Young Pyo; Pyo Choi, Young; Priola, Suzette A

    2016-02-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent of the human prion diseases, which are fatal and transmissible neurodegenerative diseases caused by the infectious prion protein (PrP(Sc)). The origin of sCJD is unknown, although the initiating event is thought to be the stochastic misfolding of endogenous prion protein (PrP(C)) into infectious PrP(Sc). By contrast, human growth hormone-associated cases of iatrogenic CJD (iCJD) in the United Kingdom (UK) are associated with exposure to an exogenous source of PrP(Sc). In both forms of CJD, heterozygosity at residue 129 for methionine (M) or valine (V) in the prion protein gene may affect disease phenotype, onset and progression. However, the relative contribution of each PrP(C) allotype to PrP(Sc) in heterozygous cases of CJD is unknown. Using mass spectrometry, we determined that the relative abundance of PrP(Sc) with M or V at residue 129 in brain specimens from MV cases of sCJD was highly variable. This result is consistent with PrP(C) containing an M or V at residue 129 having a similar propensity to misfold into PrP(Sc) thus causing sCJD. By contrast, PrP(Sc) with V at residue 129 predominated in the majority of the UK human growth hormone associated iCJD cases, consistent with exposure to infectious PrP(Sc) containing V at residue 129. In both types of CJD, the PrP(Sc) allotype ratio had no correlation with CJD type, age at clinical onset, or disease duration. Therefore, factors other than PrP(Sc) allotype abundance must influence the clinical progression and phenotype of heterozygous cases of CJD.

  15. Detection of prions in blood from patients with variant Creutzfeldt-Jakob disease.

    PubMed

    Concha-Marambio, Luis; Pritzkow, Sandra; Moda, Fabio; Tagliavini, Fabrizio; Ironside, James W; Schulz, Paul E; Soto, Claudio

    2016-12-21

    Human prion diseases are infectious and invariably fatal neurodegenerative diseases. They include sporadic Creutzfeldt-Jakob disease (sCJD), the most common form, and variant CJD (vCJD), which is caused by interspecies transmission of prions from cattle infected by bovine spongiform encephalopathy. Development of a biochemical assay for the sensitive, specific, early, and noninvasive detection of prions (PrP(Sc)) in the blood of patients affected by prion disease is a top medical priority to increase the safety of the blood supply. vCJD has already been transmitted from human to human by blood transfusion, and the number of asymptomatic carriers of vCJD in the U.K. alone is estimated to be 1 in 2000 people. We used the protein misfolding cyclic amplification (PMCA) technique to analyze blood samples from 14 cases of vCJD and 153 controls, including patients affected by sCJD and other neurodegenerative or neurological disorders as well as healthy subjects. Our results showed that PrP(Sc) could be detected with 100% sensitivity and specificity in blood samples from vCJD patients. Detection was possible in any of the blood fractions analyzed and could be done with as little as a few microliters of sample volume. The PrP(Sc) concentration in blood was estimated to be ~0.5 pg/ml. Our findings suggest that PMCA may be useful for premortem noninvasive diagnosis of vCJD and to identify prion contamination of the blood supply. Further studies are needed to fully validate the technology.

  16. Detection of prions in blood from patients with variant Creutzfeldt-Jakob disease

    PubMed Central

    Concha-Marambio, Luis; Pritzkow, Sandra; Moda, Fabio; Tagliavini, Fabrizio; Ironside, James W.; Schulz, Paul E.; Soto, Claudio

    2017-01-01

    Human prion diseases are infectious and invariably fatal neurodegenerative diseases. They include sporadic Creutzfeldt-Jakob disease (sCJD), the most common form, and variant CJD (vCJD), which is caused by interspecies transmission of prions from cattle infected by bovine spongiform encephalopathy. Development of a biochemical assay for the sensitive, specific, early, and noninvasive detection of prions (PrPSc) in the blood of patients affected by prion disease is a top medical priority to increase the safety of the blood supply. vCJD has already been transmitted from human to human by blood transfusion, and the number of asymptomatic carriers of vCJD in the U.K. alone is estimated to be 1 in 2000 people. We used the protein misfolding cyclic amplification (PMCA) technique to analyze blood samples from 14 cases of vCJD and 153 controls, including patients affected by sCJD and other neurodegenerative or neurological disorders as well as healthy subjects. Our results showed that PrPSc could be detected with 100% sensitivity and specificity in blood samples from vCJD patients. Detection was possible in any of the blood fractions analyzed and could be done with as little as a few microliters of sample volume. The PrPSc concentration in blood was estimated to be ~0.5 pg/ml. Our findings suggest that PMCA may be useful for premortem noninvasive diagnosis of vCJD and to identify prion contamination of the blood supply. Further studies are needed to fully validate the technology. PMID:28003548

  17. Modulation of Creutzfeldt-Jakob disease prion propagation by the A224V mutation

    PubMed Central

    Watts, Joel C.; Giles, Kurt; Serban, Ana; Patel, Smita; Oehler, Abby; Bhardwaj, Sumita; Guan, Shenheng; Greicius, Michael; Miller, Bruce L.; DeArmond, Stephen J.; Geschwind, Michael D.; Prusiner, Stanley B.

    2016-01-01

    Objective Mutations in the gene encoding the prion protein (PrP) are responsible for approximately 10–15% of cases of prion disease in humans, including Creutzfeldt-Jakob disease (CJD). Here we report the discovery of a previously unreported C-terminal PrP mutation (A224V) in a CJD patient exhibiting a disease similar to the rare VV1 subtype of sporadic CJD and investigate the role of this mutation in prion replication and transmission. Methods We generated transgenic (Tg) mice expressing human PrP with the V129 polymorphism and A224V mutation, denoted Tg(HuPrP,V129,A224V) mice, and inoculated them with different subtypes of sporadic (s) CJD prions. Results Transmission of sCJD VV2 or MV2 prions was accelerated in Tg(HuPrP,V129,A224V) mice compared to Tg(HuPrP,V129) mice, with incubation periods of ~110 days and ~210 days, respectively. In contrast, sCJD MM1 prions resulted in longer incubation periods in Tg(HuPrP,V129,A224V) mice compared to Tg(HuPrP,V129) mice (~320 days v. ~210 days). Prion strain fidelity was maintained in Tg(HuPrP,V129,A224V) mice inoculated with sCJD VV2 or MM1 prions, despite the altered replication kinetics. Interpretation Our results suggest that A224V is a risk factor for prion disease and modulates the transmission behavior of CJD prions in a strain-specific manner, arguing that residues near the C-terminus of PrP are important for controlling the kinetics of prion replication. PMID:26094969

  18. Altered Ca(2+) homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease.

    PubMed

    Llorens, Franc; Thüne, Katrin; Sikorska, Beata; Schmitz, Matthias; Tahir, Waqas; Fernández-Borges, Natalia; Cramm, Maria; Gotzmann, Nadine; Carmona, Margarita; Streichenberger, Nathalie; Michel, Uwe; Zafar, Saima; Schuetz, Anna-Lena; Rajput, Ashish; Andréoletti, Olivier; Bonn, Stefan; Fischer, Andre; Liberski, Pawel P; Torres, Juan Maria; Ferrer, Isidre; Zerr, Inga

    2017-04-27

    Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrP(Sc)). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca(2+)) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis.Here we describe the presence of massive regulation of Ca(2+) responsive genes in sCJD brain tissue, accompanied by two Ca(2+)-dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain proteins activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Additionally, Calpain 1 treatment enhances seeding activity of PrP(Sc) in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons, although massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca(2+) homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model.Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention.

  19. Genetic variability of the gene cluster CALHM1–3 in sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Calero, Olga; Bullido, María J.; Clarimón, Jordi; Hortigüela, Rafael; Frank-García, Ana; Martínez-Martín, Pablo; Lleó, Alberto; Rey, María Jesús; Sastre, Isabel; Rábano, Alberto; de Pedro-Cuesta, Jesús; Ferrer, Isidro; Calero, Miguel

    2012-01-01

    Perturbations of calcium homeostasis have been associated with several neurodegenerative disorders. A common polymorphism (rs2986017) in the CALHM1 gene, coding for a regulator of calcium homeostasis, is a genetic risk factor for the development of Alzheimer disease (AD). Although some authors failed to confirm these results, a meta-analysis has shown that this polymorphism modulates the age at disease onset. Furthermore, a recent association study has explored the genetic variability of CALHM1 gene and two adjacent paralog genes (CALHM3 and CALHM2) in an Asian population. Since several lines of evidence suggest that AD and prion diseases share pathophysiologic mechanisms, we investigated for the first time the genetic variability of the gene cluster formed by CALHM1 and its paralogs in a series of 235 sporadic Creutzfeldt-Jakob disease (sCJD) patients, and compared the genotypic and allelic frequencies with those presented in 329 controls from the same ancestry. As such, this work also represents the first association analysis of CALHM genes in sCJD. Sequencing analysis of the complete coding regions of the genes demonstrated the presence of 10 single nucleotide polymorphisms (SNP) within the CALHM genes. We observed that rs4918016-rs2986017-rs2986018 and rs41287502-rs41287500 polymorphic sites at CALHM1 were in linkage disequilibrium. We found marginal associations for sCJD risk at CALHM1 polymorphic sites rs41287502 and rs41287500 [coding for two linked missense mutations (p.(Met323Ile); (Gly282Cys)], and rs2986017 [p.(Leu86Pro)]. Interestingly, a TGG haplotype defined by the rs4918016-rs2986017-rs2986018 block was associated with sCJD. These findings underscore the need of future multinational collaborative initiatives in order to corroborate these seminal data. PMID:22874670

  20. Characterization of sleep disorders in patients with E200K familial Creutzfeldt-Jakob disease.

    PubMed

    Cohen, Oren S; Chapman, Joab; Korczyn, Amos D; Warman-Alaluf, Naama; Orlev, Yael; Givaty, Gili; Nitsan, Zeev; Appel, Shmuel; Rosenmann, Hanna; Kahana, Esther; Shechter-Amir, Dalia

    2015-02-01

    The largest cluster of E200K familial Creutzfeldt-Jakob disease (fCJD) which occurs is in Jews of Libyan origin in Israel. Insomnia is a very common early complaint in those patients and may even be the presenting symptom. The aim of this study was to assess and characterize sleep pathology in E200K fCJD patients. To do so, sleep studies of 10 consecutive fCJD patients were compared with those of 39 age and gender-matched controls. All patients presented pathological sleep characterized by fragmentation of sleep, loss of sleep spindles and reduced REM sleep amount. Respiration was characterized by irregular rhythm, periodic breathing, apneas and hypopneas, either central or obstructive. EMG recordings revealed repeated movements in sleep, with loss of REM atonia. Comparing to controls, a significant decrease of total sleep time, sleep efficacy and slow-wave sleep as well as a significant increase in the number of awakenings, apnea-hypopnea index and mixed and central apneas were evident in CJD patients. Comparison of two sequential sleep studies in one patient revealed a 40 % reduction of the total sleep time, a 40 % reduction in sleep efficacy and a 40-fold increase of the number of arousals in the second study. A significant correlation was found between the disease severity, as reflected by the CJD Neurological Scale and Periodic leg movement index. These definite and characteristic sleep pathologies in patients with fCJD associated with the E200K mutation may serve as a new diagnostic tool in the disease.

  1. Bioassay studies support the potential for iatrogenic transmission of variant Creutzfeldt Jakob Disease through dental procedures.

    PubMed

    Kirby, Elizabeth; Dickinson, Joanne; Vassey, Matthew; Dennis, Mike; Cornwall, Mark; McLeod, Neil; Smith, Andrew; Marsh, Philip D; Walker, James T; Sutton, J Mark; Raven, Neil D H

    2012-01-01

    Evidence is required to quantify the potential risks of transmission of variant Creutzfeldt Jakob (vCJD) through dental procedures. Studies, using animal models relevant to vCJD, were performed to address two questions. Firstly, whether oral tissues could become infectious following dietary exposure to BSE? Secondly, would a vCJD-contaminated dental instrument be able to transmit disease to another patient? BSE-301V was used as a clinically relevant model for vCJD. VM-mice were challenged by injection of infected brain homogenate into the small intestine (Q1) or by five minute contact between a deliberately-contaminated dental file and the gingival margin (Q2). Ten tissues were collected from groups of challenged mice at three or four weekly intervals, respectively. Each tissue was pooled, homogenised and bioassayed in indicator mice. Challenge via the small intestine gave a transmission rate of 100% (mean incubation 157±17 days). Infectivity was found in both dental pulp and the gingival margin within 3 weeks of challenge and was observed in all tissues tested within the oral cavity before the appearance of clinical symptoms. Following exposure to deliberately contaminated dental files, 97% of mice developed clinical disease (mean incubation 234±33 days). Infectivity was higher than expected, in a wider range of oral tissues, than was allowed for in previous risk assessments. Disease was transmitted following transient exposure of the gingiva to a contaminated dental file. These observations provide evidence that dental procedures could be a route of cross-infection for vCJD and support the enforcement of single-use for certain dental instruments.

  2. Familial Creutzfeldt-Jakob Disease: Case report and role of genetic counseling in post mortem testing.

    PubMed

    Clift, Kristin; Guthrie, Kimberly; Klee, Eric W; Boczek, Nicole; Cousin, Margot; Blackburn, Patrick; Atwal, Paldeep

    2016-11-01

    Here we present a case of an asymptomatic 53-year-old woman who sought genetic testing for Familial Creutzfeldt-Jakob Disease (fCJD) after learning that her mother had fCJD. The patient's mother had a sudden onset of memory problems and rapidly deteriorating mental faculties in her late 70s, which led to difficulties ambulating, progressive non-fluent aphasia, dysphagia and death within ∼1 y of symptom onset. The cause of death was reported as "rapid onset dementia." The patient's family, unhappy with the vague diagnosis, researched prion disorders online and aggressively pursued causation and submitted frozen brain tissue from the mother to the National Prion Disease Surveillance Center, where testing revealed a previously described 5-octapeptide repeat insertion (5-OPRI) in the prion protein gene (PRNP) that is known to cause fCJD. The family had additional questions about the implications of this result and thus independently sought out genetic counseling.  While rare, fCJD is likely underdiagnosed due to clinical heterogeneity, rapid onset, early non-specific symptomatology, and overlap in the differential diagnosis of Alzheimer disease and Lewy body dementias. When fCJD is identified, a multidisciplinary approach to return of results that includes the affected patient's provider, genetics professionals, and mental health professionals is key to the care of the family. We present an example case which discusses the psychosocial issues encountered and the role of genetic counseling in presymptomatic testing for incurable neurodegenerative conditions. Ordering physicians should be aware of the basic issues surrounding presymptomatic genetic testing and identify local genetic counseling resources for their patients.

  3. Bioassay Studies Support the Potential for Iatrogenic Transmission of Variant Creutzfeldt Jakob Disease through Dental Procedures

    PubMed Central

    Vassey, Matthew; Dennis, Mike; Cornwall, Mark; McLeod, Neil; Smith, Andrew; Marsh, Philip D.; Walker, James T.; Sutton, J. Mark; Raven, Neil D. H.

    2012-01-01

    Background Evidence is required to quantify the potential risks of transmission of variant Creutzfeldt Jakob (vCJD) through dental procedures. Studies, using animal models relevant to vCJD, were performed to address two questions. Firstly, whether oral tissues could become infectious following dietary exposure to BSE? Secondly, would a vCJD-contaminated dental instrument be able to transmit disease to another patient? Methods BSE-301V was used as a clinically relevant model for vCJD. VM-mice were challenged by injection of infected brain homogenate into the small intestine (Q1) or by five minute contact between a deliberately-contaminated dental file and the gingival margin (Q2). Ten tissues were collected from groups of challenged mice at three or four weekly intervals, respectively. Each tissue was pooled, homogenised and bioassayed in indicator mice. Findings Challenge via the small intestine gave a transmission rate of 100% (mean incubation 157±17 days). Infectivity was found in both dental pulp and the gingival margin within 3 weeks of challenge and was observed in all tissues tested within the oral cavity before the appearance of clinical symptoms. Following exposure to deliberately contaminated dental files, 97% of mice developed clinical disease (mean incubation 234±33 days). Interpretation Infectivity was higher than expected, in a wider range of oral tissues, than was allowed for in previous risk assessments. Disease was transmitted following transient exposure of the gingiva to a contaminated dental file. These observations provide evidence that dental procedures could be a route of cross-infection for vCJD and support the enforcement of single-use for certain dental instruments. PMID:23226225

  4. Genetic Cross-Interaction between APOE and PRNP in Sporadic Alzheimer's and Creutzfeldt-Jakob Diseases

    PubMed Central

    Calero, Olga; Bullido, María J.; Clarimón, Jordi; Frank-García, Ana; Martínez-Martín, Pablo; Lleó, Alberto; Rey, María Jesús; Rábano, Alberto; Blesa, Rafael; Gómez-Isla, Teresa; Valdivieso, Fernando; de Pedro-Cuesta, Jesús; Ferrer, Isidro; Calero, Miguel

    2011-01-01

    Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD) represent two distinct clinical entities belonging to a wider group, generically named as conformational disorders that share common pathophysiologic mechanisms. It is well-established that the APOE ε4 allele and homozygosity at polymorphic codon 129 in the PRNP gene are the major genetic risk factors for AD and human prion diseases, respectively. However, the roles of PRNP in AD, and APOE in CJD are controversial. In this work, we investigated for the first time, APOE and PRNP genotypes simultaneously in 474 AD and 175 sporadic CJD (sCJD) patients compared to a common control population of 335 subjects. Differences in genotype distribution between patients and control subjects were studied by logistic regression analysis using age and gender as covariates. The effect size of risk association and synergy factors were calculated using the logistic odds ratio estimates. Our data confirmed that the presence of APOE ε4 allele is associated with a higher risk of developing AD, while homozygosity at PRNP gene constitutes a risk for sCJD. Opposite, we found no association for PRNP with AD, nor for APOE with sCJD. Interestingly, when AD and sCJD patients were stratified according to their respective main risk genes (APOE for AD, and PRNP for sCJD), we found statistically significant associations for the other gene in those strata at higher previous risk. Synergy factor analysis showed a synergistic age-dependent interaction between APOE and PRNP in both AD (SF = 3.59, p = 0.027), and sCJD (SF = 7.26, p = 0.005). We propose that this statistical epistasis can partially explain divergent data from different association studies. Moreover, these results suggest that the genetic interaction between APOE and PRNP may have a biological correlate that is indicative of shared neurodegenerative pathways involved in AD and sCJD. PMID:21799773

  5. Proteomic analysis of host brain components that bind to infectious particles in Creutzfeldt-Jakob disease.

    PubMed

    Kipkorir, Terry; Colangelo, Christopher M; Manuelidis, Laura

    2015-09-01

    Transmissible encephalopathies (TSEs), such as Creutzfeldt-Jakob disease (CJD) and scrapie, are caused by infectious agents that provoke strain-specific patterns of disease. Misfolded host prion protein (PrP-res amyloid) is believed to be the causal infectious agent. However, particles that are stripped of PrP retain both high infectivity and viral proteins not detectable in uninfected mouse controls. We here detail host proteins bound with FU-CJD agent infectious brain particles by proteomic analysis. More than 98 proteins were differentially regulated, and 56 FU-CJD exclusive proteins were revealed after PrP, GFAP, C1q, ApoE, and other late pathologic response proteins were removed. Stripped FU-CJD particles revealed HSC70 (144× the uninfected control), cyclophilin B, an FU-CJD exclusive protein required by many viruses, and early endosome-membrane pathways known to facilitate viral processing, replication, and spread. Synaptosomal elements including synapsin-2 (at 33×) and AP180 (a major FU-CJD exclusive protein) paralleled the known ultrastructural location of 25 nm virus-like TSE particles and infectivity in synapses. Proteins without apparent viral or neurodegenerative links (copine-3), and others involved in viral-induced protein misfolding and aggregation, were also identified. Human sCJD brain particles contained 146 exclusive proteins, and heat shock, synaptic, and viral pathways were again prominent, in addition to Alzheimer, Parkinson, and Huntington aggregation proteins. Host proteins that bind TSE infectious particles can prevent host immune recognition and contribute to prolonged cross-species transmissions (the species barrier). Our infectious particle strategy, which reduces background sequences by >99%, emphasizes host targets for new therapeutic initiatives. Such therapies can simultaneously subvert common pathways of neurodegeneration.

  6. Cell death signaling in the cerebellum in Creutzfeldt-Jakob disease.

    PubMed

    Puig, B; Ferrer, I

    2001-09-01

    Examination of the expression of proteins linked with signaling pathways commanding cell death and cell survival has been carried out to increase understanding on the mechanisms leading to cell death in the cerebellum in Creutzfeldt-Jakob disease (CJD). Expression of Fas, Fas ligand (Fas-L), ERK, MEK, Bcl-2, Bax, N-myc, c-myc, pro-caspase-2 and active caspase-3 was examined by immunohistochemistry in the cerebellum of six patients with sporadic CJD, three patients with olivopontocerebellar atrophy (OPCA) and six age-matched controls. No modifications in the expression of these proteins were observed in granule cells in CJD and OPCA when compared with controls, except in a few cells in the molecular and granular layers in CJD that displayed dense homogeneous active caspase-3 immunostaining. This suggests selective activation of caspase-3 in association with increased cellular vulnerability in CJD. No modifications in pro-caspase-2 and c-myc immunoreactivity were observed in Purkinje cells in diseased brains when compared with controls. However, increased diffuse Fas, Fas-L, MEK, ERK and Bax expression, and enhanced granular active caspase-3 immunoreactivity was found in the cytoplasm of Purkinje cells in CJD. Increase in Bcl-2 and N-myc occurred in Purkinje cells in CJD and OPCA. These results indicate that enhanced Fas, Fas-L, MERK, ERK, Bax and granular active caspase-3 expression is not lethal to Purkinje cells in CJD, whereas increased Bcl-2 and N-myc does not preclude per se cell death or death survival in CJD and OPCA. These findings point to the likelihood that expression of these cell death proteins in neurodegeneration has functional roles differing from those related with apoptosis.

  7. Neuropathological and biochemical criteria to identify acquired Creutzfeldt-Jakob disease among presumed sporadic cases.

    PubMed

    Kobayashi, Atsushi; Parchi, Piero; Yamada, Masahito; Mohri, Shirou; Kitamoto, Tetsuyuki

    2016-06-01

    As an experimental model of acquired Creutzfeldt-Jakob disease (CJD), we performed transmission studies of sporadic CJD using knock-in mice expressing human prion protein (PrP). In this model, the inoculation of the sporadic CJD strain V2 into animals homozygous for methionine at polymorphic codon 129 (129 M/M) of the PRNP gene produced quite distinctive neuropathological and biochemical features, that is, widespread kuru plaques and intermediate type abnormal PrP (PrP(Sc) ). Interestingly, this distinctive combination of molecular and pathological features has been, to date, observed in acquired CJD but not in sporadic CJD. Assuming that these distinctive phenotypic traits are specific for acquired CJD, we revisited the literature and found two cases showing widespread kuru plaques despite the 129 M/M genotype, in a neurosurgeon and in a patient with a medical history of neurosurgery without dura mater grafting. By Western blot analysis of brain homogenates, we revealed the intermediate type of PrP(Sc) in both cases. Furthermore, transmission properties of brain extracts from these two cases were indistinguishable from those of a subgroup of dura mater graft-associated iatrogenic CJD caused by infection with the sporadic CJD strain V2. These data strongly suggest that the two atypical CJD cases, previously thought to represent sporadic CJD, very likely acquired the disease through exposure to prion-contaminated brain tissues. Thus, we propose that the distinctive combination of 129 M/M genotype, kuru plaques, and intermediate type PrP(Sc) , represents a reliable criterion for the identification of acquired CJD cases among presumed sporadic cases.

  8. Isolated language impairment as the primary presentation of sporadic Creutzfeldt Jakob Disease.

    PubMed

    El Tawil, S; Chohan, G; Mackenzie, J; Rowe, A; Weller, B; Will, R G; Knight, R

    2017-03-01

    Sporadic Creutzfeldt Jakob Disease (sCJD) is a neurodegenerative disorder that typically presents as a rapidly progressive encephalopathy associated with various neurological features, culminating in akinetic mutism and death. Atypical cases, presenting with an isolated focal may cause diagnostic confusion. We described a series of patients with sCJD presenting with isolated language impairment. We report a patient with sCJD referred to the NCJDRSU, who presented with isolated language impairment and subsequently identified all cases of sporadic CJD on the NCJDRSU database (covering the years 1990-2012) with an isolated language impairment presentation. Nineteen patients (11 females) with sCJD (1.19% of all patients) had an isolated language disorder of at least 2 weeks duration as the first neurological symptom pattern. Mean age at onset was 68.28 years. No specific pattern of language affection was seen in these patients. Further progression usually affected more than one neurological domain, with all patients eventually developing cognitive decline and myoclonic jerks. The median duration of illness was 4 months. CSF 14.3.3 was positive and S100b level was elevated in all patients in whom it was performed. EEG and MRI showed typical features of sCJD in six patients each. Most patients showed MM genotype of PRNP codon 129. This study highlights the fact that isolated aphasia can be the first neurological symptom approximately in 1% of patients with sCJD. The diagnosis is usually made with appearance of other clinical features and investigation results, but in a small minority, these may not be apparent for relatively long periods. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. The first Japanese patient with variant Creutzfeldt-Jakob disease (vCJD).

    PubMed

    Shinde, Akiyo; Kunieda, Takenobu; Kinoshita, Yoshimi; Wate, Reika; Nakano, Satoshi; Ito, Hidefumi; Yamada, Masahito; Kitamoto, Tetsuyuki; Nakamura, Yosikazu; Matsumoto, Sadayuki; Kusaka, Hirofumi

    2009-12-01

    Eleven years after a brief visit to some European countries, a 48-year-old Japanese man developed writing difficulty, irritability and general fatigue. Then he complained of dysesthetic pains in his legs, for which benzodiazepines were prescribed. However, at the time pulvinar sign was retrospectively confirmed on brain MRI. Eighteen months after the onset, his gait became ataxic with rapid deterioration of mental status over the following several months. Thirty-one months after the onset, he became akinetic and mute with periodic synchronous discharges on EEG, and died at the age of 51. The total clinical course was approximately 43 months. Pathological examination revealed the characteristic alterations of spongiform encephalopathy, severe in the thalamus, moderate but widely spread in the cerebral cortices, and moderate in the cerebellum. Abundant amyloid plaques were easily identified in the cerebral cortex and the cerebellum on HE staining. Immunohistochemistry for abnormal prion protein (PrP(sc)) confirmed amyloid plaques in several forms, such as florid, uni- and multi-centric plaques as well as perineuronal and periaxonal deposits in the basal ganglia and synaptic patterns in the thalami. A Western blotting study identified type 2B protease-resistant PrP. This is the first Japanese patient who was definitely diagnosed as variant Creutzfeldt-Jakob disease (vCJD). The pathological findings were similar to those of previous reports of vCJD in the UK. However, the changes were much more severe both in degree and distribution, probably due to a longer duration of the illness than those in the UK.

  10. Nucleic acid binding proteins in highly purified Creutzfeldt-Jakob disease preparations.

    PubMed Central

    Sklaviadis, T; Akowitz, A; Manuelidis, E E; Manuelidis, L

    1993-01-01

    The nature of the infectious agent causing human Creutzfeldt-Jakob disease (CJD), a slowly progressive dementia, is controversial. As in scrapie, no agent-specific proteins or nucleic acids have been identified. However, biological features of exponential replication and agent strain variation, as well as physical size and density data, are most consistent with a viral structure--i.e., a nucleic acid-protein complex. It is often assumed that nuclease treatment, which does not reduce infectious titer, leaves no nucleic acids of > 50 bp. However, nucleic acids of 500-6000 bp can be extracted from highly purified infectious complexes with a mass of approximately 1.5 x 10(7) daltons. It was therefore germane to search for nucleic acid binding proteins that might protect an agent genome. We here use Northwestern blotting to show that there are low levels of nonhistone nucleic acid binding proteins in highly purified infectious 120S gradient fractions. Several nucleic acid binding proteins were clearly host encoded, whereas others were apparent only in CJD, but not in parallel preparations from uninfected brain. Small amounts of residual host Gp34 (prion protein) did not bind any 32P-labeled nucleic acid probes. Most of the minor "CJD-specific" proteins had an acidic pI, a characteristic of many viral core proteins. Such proteins deserve further study, as they probably contribute to unique properties of resistance described for these agents. It remains to be seen if any of these proteins are agent encoded. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8516321

  11. The pulvinar sign on magnetic resonance imaging in variant Creutzfeldt-Jakob disease.

    PubMed

    Zeidler, M; Sellar, R J; Collie, D A; Knight, R; Stewart, G; Macleod, M A; Ironside, J W; Cousens, S; Colchester, A C; Hadley, D M; Will, R G; Colchester, A F

    2000-04-22

    There is a need for an accurate non-invasive diagnostic test for variant Creutzfeldt-Jakob disease (vCJD). We investigated the sensitivity and specificity of bilateral pulvinar high signal on magnetic resonance imaging (MRI) for the diagnosis of vCJD. MRI from patients with vCJD and controls (patients with suspected CJD) were analysed. Scans were reviewed on two separate occasions by two neuroradiologists and scored for the distribution of changes, and likely final diagnosis. Scans from vCJD cases were reassessed to reach a consensus on all abnormalities. We analysed 36 patients and 57 controls. vCJD patients were correctly identified based on bilateral pulvinar high signal in 29 of 36 and 32 of 36 cases on the first assessment by the two radiologists, and 32 of 36 and 31 of 36 on their second assessment. Bilateral increased pulvinar signal was identified in one of 57 and one of 57 controls on the first assessment and two of 57 and three of 57 controls on the second assessment. These reported changes in controls were graded as minimal/equivocal in six of seven patients and moderate in one (<0.5% of all control assessments). 80% of the assessments in vCJD cases were graded as moderate or substantial. On consensus review, 28 of 36 cases and none of 57 controls had prominent bilateral pulvinar signal-sensitivity 78% (95% CI 60-90%) and specificity 100% (95% CI 94-100%). Other common MRI features of vCJD were medial thalamic and periaqueductal grey matter high signal, and the notable absence of cerebral atrophy. Pulvinar high signal correlated with histological gliosis. In the appropriate clinical context the MRI identification of bilaterally increased pulvinar signal is a useful non-invasive test for the diagnosis of vCJD.

  12. Myoclonus in Creutzfeldt-Jakob disease: polygraphic and video-electroencephalography assessment of 109 patients.

    PubMed

    Binelli, Simona; Agazzi, Pamela; Canafoglia, Laura; Scaioli, Vidmer; Panzica, Ferruccio; Visani, Elisa; Di Fede, Giuseppe; Giaccone, Giorgio; Bizzi, Alberto; Bugiani, Orso; Avanzini, Guiliano; Tagliavini, Fabrizio; Franceschetti, Silvana

    2010-12-15

    We used electroencephalography (EEG)-polygraphic recordings to classify myoclonus in 109 patients with Creutzfeldt-Jakob disease (CJD) on the basis of its electromyography (EMG) pattern, time course, distribution, and EEG correlates. We recorded myoclonic jerks in 55 patients (50.4%), and we classified them as periodic myoclonus in 28, rhythmic in 13, and irregular in 20 (6 patients showed two types of myoclonus). Myoclonus occurred as a prominently negative event (interrupting the EMG discharge) in 10. Periodic sharp-wave complexes (PSWCs) were present in all but one patient with myoclonic jerks but were time-locked with EMG-bursts only in case of periodic myoclonus. Jerk-locked back averaging revealed a variable EEG-EMG transfer-time commonly exceeding that characterizing cortical myoclonus. Myoclonus was frequently associated with Met/Met polymorphism at codon 129 of the prion protein gene, but it was also observed in association with Met/Val or Val/Val polymorphisms provided that the EEG showed the presence of the PSWC pattern. The presence of enlarged somatosensory evoked potentials significantly correlated with the myoclonic presentation, as did MR signal hyperintensity involving the cortical mantle. Our observations on the basis of standard polygraphic criteria suggest that CJD associates with a remarkable variety of myoclonic jerks, and therefore different brain structures are probably involved as generators. The significant association between the presence of all myoclonus types with PSWCs suggests that hyperexcitable corticosubcortical loops are always required to generate (or allow) both myoclonus and the EEG complexes, either they are time locked or not.

  13. Patient with rapidly evolving neurological disease with neuropathological lesions of Creutzfeldt-Jakob disease, Lewy body dementia, chronic subcortical vascular encephalopathy and meningothelial meningioma.

    PubMed

    Vita, Maria Gabriella; Tiple, Dorina; Bizzarro, Alessandra; Ladogana, Anna; Colaizzo, Elisa; Capellari, Sabina; Rossi, Marcello; Parchi, Piero; Masullo, Carlo; Pocchiari, Maurizio

    2017-04-01

    We report a case of rapidly evolving neurological disease in a patient with neuropathological lesions of Creutzfeldt-Jakob disease (CJD), Lewy body dementia (LBD), chronic subcortical vascular encephalopathy and meningothelial meningioma. The coexistence of severe multiple pathologies in a single patient strengthens the need to perform accurate clinical differential diagnoses in rapidly progressive dementias. © 2016 Japanese Society of Neuropathology.

  14. Altered Prion Protein Expression Pattern in CSF as a Biomarker for Creutzfeldt-Jakob Disease

    PubMed Central

    Torres, Mauricio; Cartier, Luis; Matamala, José Manuel; Hernández, Nancy; Woehlbier, Ute; Hetz, Claudio

    2012-01-01

    Creutzfeldt-Jakob disease (CJD) is the most frequent human Prion-related disorder (PrD). The detection of 14-3-3 protein in the cerebrospinal fluid (CSF) is used as a molecular diagnostic criterion for patients clinically compatible with CJD. However, there is a pressing need for the identification of new reliable disease biomarkers. The pathological mechanisms leading to accumulation of 14-3-3 protein in CSF are not fully understood, however neuronal loss followed by cell lysis is assumed to cause the increase in 14-3-3 levels, which also occurs in conditions such as brain ischemia. Here we investigated the relation between the levels of 14-3-3 protein, Lactate dehydrogenase (LDH) activity and expression of the prion protein (PrP) in CSF of sporadic and familial CJD cases. Unexpectedly, we found normal levels of LDH activity in CJD cases with moderate levels of 14-3-3 protein. Increased LDH activity was only observed in a percentage of the CSF samples that also exhibited high 14-3-3 levels. Analysis of the PrP expression pattern in CSF revealed a reduction in PrP levels in all CJD cases, as well as marked changes in its glycosylation pattern. PrP present in CSF of CJD cases was sensitive to proteases. The alterations in PrP expression observed in CJD cases were not detected in other pathologies affecting the nervous system, including cases of dementia and tropical spastic paraparesis/HTLV-1 associated myelopathy (HAM/TSP). Time course analysis in several CJD patients revealed that 14-3-3 levels in CSF are dynamic and show a high degree of variability during the end stage of the disease. Post-mortem analysis of brain tissue also indicated that 14-3-3 protein is upregulated in neuronal cells, suggesting that its expression is modulated during the course of the disease. These results suggest that a combined analysis of 14-3-3 and PrP expression pattern in CSF is a reliable biomarker to confirm the clinical diagnosis of CJD patients and follow disease progression

  15. Ocular Tonometry and Sporadic Creutzfeldt - Jakob Disease (sCJD): A Confirmatory Case-Control Study.

    PubMed

    Davanipour, Zoreh; Sobel, Eugene; Ziogas, Argyrios; Smoak, Carey; Bohr, Thomas; Doram, Keith; Liwnicz, Boleslaw

    2014-04-30

    To evaluate the hypothesis that sporadic Creutzfeldt-Jakob disease (sCJD) may be transmitted through ocular tonometry. The infectious agent of sCJD may be present in the cornea prior to clinical symptoms. Cornea infectiousness has been documented by cornea transplants in guinea pigs and humans. sCJD is resistant to complete inactivity by conventional sterilization techniques. Thus contact tonometry equipment is not disinfected sufficiently to kill sCJD. We previously hypothesized that contact tonometry is a sCJD risk factor. Population-based case-control study. Department of Neurology, School of Medicine, Loma Linda University, Loma Linda, CA, USA; 4 years. An 11-state case-control study of pathologically confirmed definite sCJD cases, individually matched controls, and a sample of control surrogates was conducted. Ocular tonometry histories were obtained from case-surrogates, controls, and a sample of control-surrogates. The odds ratio (OR) for ever vs never having had an ocular tonometry test was statistically significant for matched and unmatched analyses for 15 through 3 years prior to disease onset, using both control self-responses and control surrogates: ORs were ∞ and 19.4 with 1-sided P-values <0.0001 and 0.003 and ORs=∞ and 11.1 with 1-sided P-values <0.003 and 0.02, respectively. ORs increased as the number of tonometry tests increased during this age period: trend test, 2-sided P-value < 0.0001. For ≥5 vs <5 tonometry tests, the OR was 5.8 (unmatched) and 3.7 (matched), 2-sided P-value<0.00005. Respondents generally could not specify the type of tonometry. There was no indication of increased tonometry testing among cases within 2 years of disease onset. The a priori hypothesis was supported. Contact tonometry, preferred by ophthalmologists, may be capable of transmitting sCJD. Consideration should be given to using disposable instrument covers after each use. The use the disposable covers or non-contact tonometry is preferable in the absence of

  16. A Genome Wide Association Study Links Glutamate Receptor Pathway to Sporadic Creutzfeldt-Jakob Disease Risk

    PubMed Central

    Sanchez-Juan, Pascual; Bishop, Matthew T.; Kovacs, Gabor G.; Calero, Miguel; Aulchenko, Yurii S.; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, Claudia; Calero, Olga; Poleggi, Anna; Carracedo, Ángel; van der Lee, Sven J.; Ströbel, Thomas; Rivadeneira, Fernando; Hofman, Albert; Haïk, Stéphane; Combarros, Onofre; Berciano, José; Uitterlinden, Andre G.; Collins, Steven J.; Budka, Herbert; Brandel, Jean-Philippe; Laplanche, Jean Louis; Pocchiari, Maurizio; Zerr, Inga; Knight, Richard S. G.; Will, Robert G.; van Duijn, Cornelia M.

    2015-01-01

    We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis. PMID:25918841

  17. A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk.

    PubMed

    Sanchez-Juan, Pascual; Bishop, Matthew T; Kovacs, Gabor G; Calero, Miguel; Aulchenko, Yurii S; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, Claudia; Calero, Olga; Poleggi, Anna; Carracedo, Ángel; van der Lee, Sven J; Ströbel, Thomas; Rivadeneira, Fernando; Hofman, Albert; Haïk, Stéphane; Combarros, Onofre; Berciano, José; Uitterlinden, Andre G; Collins, Steven J; Budka, Herbert; Brandel, Jean-Philippe; Laplanche, Jean Louis; Pocchiari, Maurizio; Zerr, Inga; Knight, Richard S G; Will, Robert G; van Duijn, Cornelia M

    2014-01-01

    We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis.

  18. Postmortem findings in a case of variant Creutzfeldt-Jakob disease treated with intraventricular pentosan polysulfate

    PubMed Central

    Newman, P K; Todd, N V; Scoones, D; Mead, S; Knight, R S G; Will, R G; Ironside, J W

    2014-01-01

    Background A small number of patients with variant Creutzfeldt-Jakob disease (vCJD) have been treated with intraventicular pentosan polysulfate (iPPS) and extended survival has been reported in some cases. To date, there have been no reports on the findings of postmortem examination of the brain in treated patients and the reasons for the extended survival are uncertain. We report on the neuropathological findings in a case of vCJD treated with PPS. Methods Data on survival in vCJD is available from information held at the National CJD Research and Surveillance Unit and includes the duration of illness in 176 cases of vCJD, five of which were treated with iPPS. One of these individuals, who received iPPS for 8 years and lived for 105 months, underwent postmortem examination, including neuropathological examination of the brain. Results The mean survival in vCJD is 17 months, with 40 months the maximum survival in patients not treated with PPS. In the 5 patients treated with PPS survival was 16 months, 45 months, 84 months, 105 months and 114 months. The patient who survived 105 months underwent postmortem examination which confirmed the diagnosis of vCJD and showed severe, but typical, changes, including neuronal loss, astrocytic gliosis and extensive prion protein (PrP) deposition in the brain. The patient was also given PPS for a short period by peripheral infusion and there was limited PrP immunostaining in lymphoreticular tissues such as spleen and appendix. Conclusions Treatment with iPPS did not reduce the overall neuropathological changes in the brain. The reduced peripheral immunostaining for PrP may reflect atrophy of these tissues in relation to chronic illness rather than a treatment effect. The reason for the long survival in patients treated with iPPS is unclear, but a treatment effect on the disease process cannot be excluded. PMID:24554103

  19. Dietary Risk Factors for Sporadic Creutzfeldt-Jakob Disease: A Confirmatory Case-Control Study

    PubMed Central

    Davanipour, Zoreh; Sobel, Eugene; Ziogas, Argyrios; Smoak, Carey; Bohr, Thomas; Doram, Keith; Liwnicz, Boleslaw

    2014-01-01

    Aims This study’s primary purpose was to determine whether earlier findings suggesting an association between sporadic Creutzfeldt-Jakob disease (sCJD), a transmissible spongiform encephalopathy of humans and specific dietary components could be replicated. The a priori hypotheses were that consumption of (i) foods likely to contain organ tissue and (ii) raw/rare meat are associated with increased sCJD risk. Study Design Population-based case-control study. Place and Duration of Study Department of Neurology, School of Medicine, Loma Linda University, Loma Linda, CA, USA; 4 years. Methodology An 11-state case-control study of pathologically confirmed, definite sCJD cases, matched controls, and a sample of control-surrogates was conducted. Ninety-six percent (106/110) of the case data was obtained in 1991-1993, prior to variant CJD publicity. Results Using control self-responses, consumption of hot dogs, sausage, pepperoni, kielbasa, “other” canned meat, poultry liver, any stomach/intestine, beef stomach/intestine, any organ tissue, and beef organ tissue was individually associated with increased sCJD risk; odds ratios (OR) ranged from 2.4 to 7.2 (0.003

  20. Determination of neuronal antibodies in suspected and definite Creutzfeldt-Jakob disease.

    PubMed

    Grau-Rivera, Oriol; Sánchez-Valle, Raquel; Saiz, Albert; Molinuevo, José Luis; Bernabé, Reyes; Munteis, Elvira; Pujadas, Francesc; Salvador, Antoni; Saura, Júlia; Ugarte, Antonio; Titulaer, Maarten; Dalmau, Josep; Graus, Francesc

    2014-01-01

    Creutzfeldt-Jakob disease (CJD) and autoimmune encephalitis with antibodies against neuronal surface antigens (NSA-abs) may present with similar clinical features. Establishing the correct diagnosis has practical implications in the management of care for these patients. To determine the frequency of NSA-abs in the cerebrospinal fluid of patients with suspected CJD and in patients with pathologically confirmed (ie, definite) CJD. A mixed prospective (suspected) and retrospective (definite) CJD cohort study was conducted in a reference center for detection of NSA-abs. The population included 346 patients with suspected CJD and 49 patients with definite CJD. Analysis of NSA-abs in cerebrospinal fluid with brain immunohistochemistry optimized for cell-surface antigens was performed. Positive cases in the suspected CJD group were further studied for antigen specificity using cell-based assays. All definite CJD cases were comprehensively tested for NSA-abs, with cell-based assays used for leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), N-methyl-d-aspartate (NMDA), and glycine (GlY) receptors. Neuronal surface antigens were detected in 6 of 346 patients (1.7%) with rapid neurologic deterioration suggestive of CJD. None of these 6 patients fulfilled the diagnostic criteria for probable or possible CJD. The target antigens included CASPR2, LGI1, NMDAR, aquaporin 4, Tr (DNER [δ/notch-like epidermal growth factor-related receptor]), and an unknown protein. Four of the patients developed rapidly progressive dementia, and the other 2 patients had cerebellar ataxia or seizures that were initially considered to be myoclonus without cognitive decline. The patient with Tr-abs had a positive 14-3-3 test result. Small cell lung carcinoma was diagnosed in the patient with antibodies against an unknown antigen. All patients improved or stabilized after appropriate treatment. None of the 49 patients with definite CJD had NSA-abs. A low, but

  1. Ultrastructural study of florid plaques in variant Creutzfeldt-Jakob disease: a comparison with amyloid plaques in kuru, sporadic Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease.

    PubMed

    Sikorska, B; Liberski, P P; Sobów, T; Budka, H; Ironside, J W

    2009-02-01

    Although the histological features of the amyloid plaques in variant Creutzfeldt-Jakob disease (vCJD) are distinct from those in other forms of prion disease [kuru, sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Sträussler-Scheinker disease (GSS)], their ultrastructural features have only been described in a single case report. To study vCJD plaques systematically and compare them with plaques in kuru, sCJD, GSS and Alzheimer disease (AD). Amyloid plaques were studied by transmission electron microscopy and image analysis in five cases of vCJD, three cases of GSS, two cases of sCJD, one case of kuru and five cases of AD. Immunohistochemistry was performed on paraffin sections from one case of vCJD, two cases of GSS, one case of kuru and two cases of sCJD. The florid plaques in vCJD were either compact or more diffuse; in both forms, the radiating fibrils were organized into thick 'tongues', in contrast to kuru plaques. Dystrophic neurites (DNs) containing lysosomal electron-dense bodies or vesicles surrounded florid plaques. Microglial cells were found within florid plaques; occasional amyloid fibrils were identified in membrane-bound pockets of microglial cells. In vCJD, there was significant tau immunoreactivity in DNs around florid plaques while, in sCJD, GSS and kuru, minimal tau immunoreactivity was observed around plaques. The ultrastructure of the florid plaques and DNs in vCJD is more reminiscent of neuritic plaques in AD than kuru or multicentric plaques. These findings may reflect differences both in the strains of the transmissible agents responsible for these disorders and in host factors.

  2. Iatrogenic and sporadic Creutzfeldt-Jakob disease in 2 sisters without mutation in the prion protein gene.

    PubMed

    Frontzek, Karl; Moos, Rita; Schaper, Elke; Jann, Lukas; Herfs, Gregor; Zimmermann, Dieter R; Aguzzi, Adriano; Budka, Herbert

    2015-01-01

    Human genetic prion diseases have invariably been linked to alterations of the prion protein (PrP) gene PRNP. Two sisters died from probable Creutzfeldt-Jakob disease (CJD) in Switzerland within 14 y. At autopsy, both patients had typical spongiform change in their brains accompanied by punctuate deposits of PrP. Biochemical analyses demonstrated proteinase K-resistant PrP. Sequencing of PRNP showed 2 wild-type alleles in both siblings. Retrospectively, clinical data revealed a history of dural transplantation in the initially deceased sister, compatible with a diagnosis of iatrogenic CJD. Clinical and familial histories provided no evidence for potential horizontal transmission. This observation of 2 siblings suffering from CJD without mutations in the PRNP gene suggests potential involvement of non-PRNP genes in prion disease etiology.

  3. Kuru prions and sporadic Creutzfeldt-Jakob disease prions have equivalent transmission properties in transgenic and wild-type mice.

    PubMed

    Wadsworth, Jonathan D F; Joiner, Susan; Linehan, Jacqueline M; Desbruslais, Melanie; Fox, Katie; Cooper, Sharon; Cronier, Sabrina; Asante, Emmanuel A; Mead, Simon; Brandner, Sebastian; Hill, Andrew F; Collinge, John

    2008-03-11

    Kuru provides our principal experience of an epidemic human prion disease and primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. Kuru was transmitted by the practice of consuming dead relatives as a mark of respect and mourning (transumption). To date, detailed information of the prion strain type propagated in kuru has been lacking. Here, we directly compare the transmission properties of kuru prions with sporadic, iatrogenic, and variant Creutzfeldt-Jakob disease (CJD) prions in Prnp-null transgenic mice expressing human prion protein and in wild-type mice. Molecular and neuropathological data from these transmissions show that kuru prions are distinct from variant CJD and have transmission properties equivalent to those of classical (sporadic) CJD prions. These findings are consistent with the hypothesis that kuru originated from chance consumption of an individual with sporadic CJD.

  4. Creutzfeldt-Jakob disease associated with a V203I homozygous mutation in the prion protein gene.

    PubMed

    Komatsu, Junji; Sakai, Kenji; Hamaguchi, Tsuyoshi; Sugiyama, Yu; Iwasa, Kazuo; Yamada, Masahito

    2014-01-01

    We report a Japanese patient with Creutzfeldt-Jakob disease (CJD) with a V203I homozygous mutation of the prion protein gene (PRNP). A 73-year-old woman developed rapidly progressive gait disturbance and cognitive dysfunction. Four months after the onset, she entered a state of an akinetic mutism. Gene analysis revealed a homozygous V203I mutation in the PRNP. Familial CJD with a V203I mutation is rare, and all previously reported cases had a heterozygous mutation showing manifestations similar to those of typical sporadic CJD. Although genetic prion diseases with homozygous PRNP mutations often present with an earlier onset and more rapid clinical course than those with heterozygous mutations, no difference was found in clinical phenotype between our homozygous case and reported heterozygous cases.

  5. Novel prion protein gene mutation at codon 196 (E196A) in a septuagenarian with Creutzfeldt-Jakob disease.

    PubMed

    Zhang, Hongliang; Wang, Meibo; Wu, Limin; Zhang, Haining; Jin, Tao; Wu, Jiang; Sun, Li

    2014-01-01

    Creutzfeldt-Jakob disease (CJD) is a rare and rapidly progressive neurodegenerative disease of the central nervous system, which may occur in inherited, acquired (variant and iatrogenic), or spontaneous (sporadic) forms. We report a 76-year-old Chinese man with CJD found to have a novel mutation in the prion protein gene (PRNP). The 14-3-3 protein was positive in the cerebrospinal fluid; diffusion-weighted MRI revealed ribbon-like high signal intensity in the bilateral cortices; and electroencephalography showed typical periodic synchronous discharge. CJD was diagnosed based on characteristic clinical manifestations. Interestingly, a point mutation of PRNP at codon 196 (E196A: GAG→GCG) was detected. In conclusion, we identified a patient with CJD with a novel PRNP mutation, which expands the spectrum of PRNP mutations in CJD.

  6. Creutzfeldt-Jakob Disease in a Tertiary Care Hospital in Thailand: A Case Series and Review of the Literature.

    PubMed

    Lolekha, Praween; Rasheed, Ahmed; Yotsarawat, Chutanat

    2015-09-01

    Creutzfeldt-Jakob Disease (CJD) is an incurable and inevitably fatal neurodegenerative disorder. Although CJD has a worldwide distribution, there are no official statistics on CJD in Thailand. A diagnosis of CJD is suspected when a patient develops rapidly progressive dementia with myoclonus. However, CJD may be mistaken for a variety of illnesses because its initial presentation frequently consists of non-specific symptoms. Here, we examined cases of sporadic CJD (sCJD) from Thammasat University Hospital (a tertiary care hospital in Thailand) between January 1, 2012 and December 31, 2014. Three cases of probable and possible sCJD were collected. All cases presented with rapidly progressive cognitive dysfunction accompanied by spontaneous myoclonus. Classical electroencehalography changes and typical abnormal MRI features were observed. All of the cases died within a period of 8 months. None of the patients underwent brain biopsy. Our findings raise questions about the prevalence of CJD in Thailand, which needs further study.

  7. Rare V203I mutation in the PRNP gene of a Chinese patient with Creutzfeldt-Jakob disease.

    PubMed

    Shi, Qi; Chen, Cao; Wang, Xian-Jun; Zhou, Wei; Wang, Ji-Chun; Zhang, Bao-Yun; Gao, Chen; Gao, Chen; Han, Jun; Dong, Xiao-Ping

    2013-01-01

    Here, we report a Chinese case of Creutzfeldt-Jakob disease (CJD) with a rare mutation in the prion protein gene (PRNP) leading to an exchange of amino acid from valine (Val) to isoleucine (I) at codon 203 (V203I). The 80-y-old male presented with sudden memory loss, rapid loss of vocabulary, inattention and slow responses, accompanied by dizziness, blurred vision and ataxia. Two weeks after admission, he exhibited tremor, myoclonus and bilateral Babinski signs. At the end of the clinical course, he developed severe akinetic mutism. The cerebrospinal fluid (CSF) was positive for 14-3-3 protein. Increased bilateral signal intensity in the frontal and parietal lobes was seen on diffusion-weighted imaging (DWI); periodic activity was recorded on an electroencephalogram (EEG). There was no family history of similar symptoms. The total clinical course was approximately two months.

  8. Magnetic resonance imaging reveals Creutzfeldt-Jakob disease in a patient with apparent dementia with Lewy bodies.

    PubMed

    Tsivgoulis, Georgios; Bonakis, Anastasios; Papathanasiou, Matilda A; Chondrogianni, Maria; Papageorgiou, Sokratis G; Voumvourakis, Konstantinos; Stefanis, Leonidas

    2014-05-15

    The differential diagnosis of dementia with Lewy bodies (DLB) and sporadic Creutzfeldt-Jakob disease (CJD) may be challenging. Patients with the original diagnosis of possible CJD may occasionally prove to have a pathological diagnosis of DLB, while other cases may fulfill the diagnostic clinical criteria for DLB but subsequent clinical course, cerebrospinal fluid (CSF) and neuropathology findings necessitate diagnostic revision to CJD. We describe a 79-year old patient recently diagnosed with dementia with Lewy bodies (DLB) on the basis of subacute cognitive decline, visual hallucinations and Parkinsonian features, who presented with increasing agitation. Brain neuroimaging with MRI raised the diagnostic suspicion of CJD and subsequent diagnostic work-up with electroencephalography (EEG) and CSF analysis led to the establishment of CJD diagnosis. The present case highlights the clinical utility of novel diagnostic CJD criteria that also incorporate neuroimaging findings in the diagnostic CJD panel.

  9. Creutzfeldt-Jakob disease in Japan: an epidemiological study done in a select prefecture between 1976 and 1986.

    PubMed

    Akai, J; Ishihara, O; Higuchi, S

    1989-01-01

    An epidemiological study was performed with respect to Creutzfeldt-Jakob disease in a designated area in Japan. The subjects were observed in a small rural prefecture where the population generally remains within a limited radius throughout their lives. The patients' life-styles in each area were investigated in detail. Nine cases appeared in 11 years; 6 were definitive and 3 probable. They were all of the subacute type; there were no noteworthy sexual differences, age of onset, course and/or past histories. Three of the nine cases came from two families; the relationship between familial and isolated cases was examined. Revealed facts and time-space clustering were investigated statistically, but no indication of natural transmission was observable.

  10. Diagnostic profiles of patients with late-onset Creutzfeldt-Jakob disease differ from those of younger Creutzfeldt-Jakob patients: a historical cohort study using data from the German National Reference Center.

    PubMed

    Karch, André; Raddatz, Lena Maria; Ponto, Claudia; Hermann, Peter; Summers, David; Zerr, Inga

    2014-05-01

    In contrast to other neurodegenerative diseases, sporadic Creutzfeldt-Jakob disease (sCJD) is rarely diagnosed in patients older than 75 years. Data describing the characteristics of sCJD in the very old are rare and inconclusive. Therefore, a historical cohort study was designed to evaluate clinical, cerebrospinal fluid (CSF), electroencephalography (EEG), and magnetic resonance imaging (MRI) features of this group. Patients older than 75 years identified via the German surveillance program from 2001 to 2012 (n = 73) were compared to a random subsample of sCJD patients younger than 75 (n = 73) from the same time period using an historical cohort design. Older patients showed a faster disease progression represented by an earlier point of diagnosis and a shorter survival time (p < 0.001). In the early stages of disease, older patients presented slightly more often with dementia (p = 0.127) or dysarthria (p = 0.238), whereas disorders of the extrapyramidal (p = 0.056) and visual system (p = 0.015) were more common in the younger group. Atypical MRI profiles such as MRI lesions restricted to one hemisphere (p < 0.001) or cortical lesions only (p = 0.258) were found more frequently in patients older than 75 years, whereas typical cortical and basal ganglia hyperintensities were more common in the younger group (p = 0.001). We demonstrated for the first time that patients with late-onset sCJD differ from younger sCJD patients with respect to MRI profiles and initial clinical presentation, but not among CSF markers. Misclassification of Creutzfeldt-Jakob disease cases in patients older than 75 years seems likely due to atypical clinical and radiological presentation. This might contribute to lower sCJD incidence rates in this age group.

  11. Coexistence of protease sensitive and resistant prion protein in 129VV homozygous sporadic Creutzfeldt-Jakob disease: a case report.

    PubMed

    Rodríguez-Martínez, Ana B; López de Munain, Adolfo; Ferrer, Isidro; Zarranz, Juan J; Atarés, Begoña; Villagra, Nuria T; Arteagoitia, Jose M; Garrido, Joseba M; Juste, Ramón A

    2012-10-11

    The coexistence of different molecular types of classical protease-resistant prion protein in the same individual have been described, however, the simultaneous finding of these with the recently described protease-sensitive variant or variably protease-sensitive prionopathy has, to the best of our knowledge, not yet been reported. A 74-year-old Caucasian woman showed a sporadic Creutzfeldt-Jakob disease clinical phenotype with reactive depression, followed by cognitive impairment, akinetic-rigid Parkinsonism with pseudobulbar syndrome and gait impairment with motor apraxia, visuospatial disorientation, and evident frontal dysfunction features such as grasping, palmomental reflex and brisk perioral reflexes. She died at age 77.Neuropathological findings showed: spongiform change in the patient's cerebral cortex, striatum, thalamus and molecular layer of the cerebellum with proteinase K-sensitive synaptic-like, dot-like or target-like prion protein deposition in the cortex, thalamus and striatum; proteinase K-resistant prion protein in the same regions; and elongated plaque-like proteinase K-resistant prion protein in the molecular layer of the cerebellum. Molecular analysis of prion protein after proteinase K digestion revealed decreased signal intensity in immunoblot, a ladder-like protein pattern, and a 71% reduction of PrPSc signal relative to non-digested material. Her cerebellum showed a 2A prion protein type largely resistant to proteinase K. Genotype of polymorphism at codon 129 was valine homozygous. Molecular typing of prion protein along with clinical and neuropathological data revealed, to the best of our knowledge, the first case of the coexistence of different protease-sensitive prion proteins in the same patient in a rare case that did not fulfill the current clinical diagnostic criteria for either probable or possible sporadic Creutzfeldt-Jakob disease. This highlights the importance of molecular analyses of several brain regions in order to

  12. Inherited Creutzfeldt-Jakob disease in a British family associated with a novel 144 base pair insertion of the prion protein gene.

    PubMed Central

    Nicholl, D; Windl, O; de Silva, R; Sawcer, S; Dempster, M; Ironside, J W; Estibeiro, J P; Yuill, G M; Lathe, R; Will, R G

    1995-01-01

    A case of familial Creutzfeldt-Jakob disease associated with a 144 base pair insertion in the open reading frame of the prion protein gene is described. Sequencing of the mutated allele showed an arrangement of six octapeptide repeats, distinct from that of a recently described British family with an insertion of similar size. Thirteen years previously the brother of the proband had died from "Huntington's disease", but re-examination of his neuropathology revealed spongiform encephalopathy and anti-prion protein immunocytochemistry gave a positive result. The independent evolution of at least two distinct pathological 144 base pair insertions in Britain is proposed. The importance of maintaining a high index of suspicion of inherited Creutzfeldt-Jakob disease in cases of familial neurodegenerative disease is stressed. Images PMID:7823070

  13. Lack of prion infectivity in fixed heart tissue from patients with Creutzfeldt-Jakob disease or amyloid heart disease.

    PubMed

    Priola, Suzette A; Ward, Anne E; McCall, Sherman A; Trifilo, Matthew; Choi, Young Pyo; Solforosi, Laura; Williamson, R Anthony; Cruite, Justin T; Oldstone, Michael B A

    2013-09-01

    In most forms of prion disease, infectivity is present primarily in the central nervous system or immune system organs such as spleen and lymph node. However, a transgenic mouse model of prion disease has demonstrated that prion infectivity can also be present as amyloid deposits in heart tissue. Deposition of infectious prions as amyloid in human heart tissue would be a significant public health concern. Although abnormal disease-associated prion protein (PrP(Sc)) has not been detected in heart tissue from several amyloid heart disease patients, it has been observed in the heart tissue of a patient with sporadic Creutzfeldt-Jakob Disease (sCJD), the most common form of human prion disease. In order to determine whether prion infectivity can be found in heart tissue, we have inoculated formaldehyde fixed brain and heart tissue from two sCJD patients, as well as prion protein positive fixed heart tissue from two amyloid heart disease patients, into transgenic mice overexpressing the human prion protein. Although the sCJD brain samples led to clinical or subclinical prion infection and deposition of PrP(Sc) in the brain, none of the inoculated heart samples resulted in disease or the accumulation of PrP(Sc). Thus, our results suggest that prion infectivity is not likely present in cardiac tissue from sCJD or amyloid heart disease patients.

  14. Lack of Prion Infectivity in Fixed Heart Tissue from Patients with Creutzfeldt-Jakob Disease or Amyloid Heart Disease

    PubMed Central

    Ward, Anne E.; McCall, Sherman A.; Trifilo, Matthew; Choi, Young Pyo; Solforosi, Laura; Williamson, R. Anthony; Cruite, Justin T.; Oldstone, Michael B. A.

    2013-01-01

    In most forms of prion disease, infectivity is present primarily in the central nervous system or immune system organs such as spleen and lymph node. However, a transgenic mouse model of prion disease has demonstrated that prion infectivity can also be present as amyloid deposits in heart tissue. Deposition of infectious prions as amyloid in human heart tissue would be a significant public health concern. Although abnormal disease-associated prion protein (PrPSc) has not been detected in heart tissue from several amyloid heart disease patients, it has been observed in the heart tissue of a patient with sporadic Creutzfeldt-Jakob Disease (sCJD), the most common form of human prion disease. In order to determine whether prion infectivity can be found in heart tissue, we have inoculated formaldehyde fixed brain and heart tissue from two sCJD patients, as well as prion protein positive fixed heart tissue from two amyloid heart disease patients, into transgenic mice overexpressing the human prion protein. Although the sCJD brain samples led to clinical or subclinical prion infection and deposition of PrPSc in the brain, none of the inoculated heart samples resulted in disease or the accumulation of PrPSc. Thus, our results suggest that prion infectivity is not likely present in cardiac tissue from sCJD or amyloid heart disease patients. PMID:23785217

  15. Case report of Lewy body disease mimicking Creutzfeldt-Jakob disease in a 44-year-old man.

    PubMed

    Saint-Aubert, Laure; Pariente, Jérémie; Dumas, Herve; Payoux, Pierre; Brandel, Jean-Philippe; Puel, Michèle; Vital, Anne; Guedj, Eric; Lesage, Suzanne; Peoc'h, Katell; Brefel Courbon, Christine; Ory Magne, Fabienne

    2016-07-30

    Few patients are reported with dementia with Lewy bodies before fifty years-old, which may partly reflect the difficulty of accurate diagnosis in young population. We report the case of a 44-year-old male with pathologically confirmed sporadic dementia with Lewy bodies, who did not fulfil the revised clinical criteria for this disease. We document this atypical case with clinical and cognitive evaluation, imaging, biochemistry, genetics and pathology investigations. Creutzfeldt-Jakob disease was first suspected in this patient with no previous medical history, who developed acute and rapid cognitive impairment, L-dopa-non-responsive parkinsonism, and delusion. Positive 14-3-3 protein was initially detected in cerebrospinal fluid and until the late stages of the disease. Severe atrophy with no diffusion hypersignal was found on structural MRI as well as an extensive hypometabolism on (18)F-FDG-PET, in comparison to age-matched healthy volunteers. Genetic investigation found no alpha-synuclein gene mutation. The patient died within 5 years, and post-mortem examination found numerous Lewy bodies and Lewy neurites consistent with pure Lewy body disease. This comprehensively described case illustrates that dementia with Lewy bodies can occur in young patients with atypical clinical presentation. Biochemistry and neuroimaging investigations can sometimes be insufficient to allow accurate diagnostic. More specific markers to support such diagnosis are needed.

  16. Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions.

    PubMed

    Watts, Joel C; Giles, Kurt; Saltzberg, Daniel J; Dugger, Brittany N; Patel, Smita; Oehler, Abby; Bhardwaj, Sumita; Sali, Andrej; Prusiner, Stanley B

    2016-11-01

    The biochemical and neuropathological properties of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) prions are faithfully maintained upon transmission to guinea pigs. However, primary and secondary transmissions of BSE and vCJD in guinea pigs result in long incubation periods of ∼450 and ∼350 days, respectively. To determine if the incubation periods of BSE and vCJD prions could be shortened, we generated transgenic (Tg) mice expressing guinea pig prion protein (GPPrP). Inoculation of Tg(GPPrP) mice with BSE and vCJD prions resulted in mean incubation periods of 210 and 199 days, respectively, which shortened to 137 and 122 days upon serial transmission. In contrast, three different isolates of sporadic CJD prions failed to transmit disease to Tg(GPPrP) mice. Many of the strain-specified biochemical and neuropathological properties of BSE and vCJD prions, including the presence of type 2 protease-resistant PrP(Sc), were preserved upon propagation in Tg(GPPrP) mice. Structural modeling revealed that two residues near the N-terminal region of α-helix 1 in GPPrP might mediate its susceptibility to BSE and vCJD prions. Our results demonstrate that expression of GPPrP in Tg mice supports the rapid propagation of BSE and vCJD prions and suggest that Tg(GPPrP) mice may serve as a useful paradigm for bioassaying these prion isolates. Variant Creutzfeldt-Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE) prions are two of the prion strains most relevant to human health. However, propagating these strains in mice expressing human or bovine prion protein has been difficult because of prolonged incubation periods or inefficient transmission. Here, we show that transgenic mice expressing guinea pig prion protein are fully susceptible to vCJD and BSE prions but not to sporadic CJD prions. Our results suggest that the guinea pig prion protein is a better, more rapid substrate than either bovine or human prion protein for

  17. Characteristics of Korean patients with suspected Creutzfeldt-Jakob disease with 14-3-3 protein in cerebrospinal fluid: Preliminary study of the Korean Creutzfeldt-Jakob disease active surveillance program

    PubMed Central

    Lim, Jae-Sung; Kwon, Hyung-Min; Jang, Jae-Won; Ju, Young-Ran; Kim, SuYeon; Park, Young Ho; Park, So Young; Kim, SangYun

    2015-01-01

    Abstract Although Korea had a national surveillance system for Creutzfeldt-Jakob disease (CJD), it was mainly dependent on attending physician's reports. Thus, little prospective data about the epidemiology, characteristics, and final diagnoses of suspected patients were available. We have established a nationwide network for the active surveillance of patients with suspected CJD. When the requested cerebrospinal fluid (CSF) samples tested positive for 14-3-3 protein, we investigated the clinical characteristics of the corresponding patients and followed them until their final diagnoses were confirmed. A total of 218 samples were requested for CSF assays from May 2010 to August 2012, and 106 (48.6%) were positive for 14-3-3 protein. In 89 patients with complete clinical data, 38 (42.7%) were diagnosed with probable CJD and the estimated annual occurrence of CJD was 16.3 persons-per-year. The most common diagnoses of the remainder were central nervous system infection and any-cause encephalopathy. Non-CJD subjects showed worse initial consciousness levels than CJD patients. This preliminary study showed that the number of reported cases of CJD and the true positivity rates of CSF 14-3-3 protein assays were both low in Korea. An active surveillance system is urgently needed to provide the latest nationwide epidemiological data of CJD. PMID:25996401

  18. Characteristics of Korean patients with suspected Creutzfeldt-Jakob disease with 14-3-3 protein in cerebrospinal fluid: Preliminary study of the Korean Creutzfeldt-Jakob disease active surveillance program.

    PubMed

    Lim, Jae-Sung; Kwon, Hyung-Min; Jang, Jae-Won; Ju, Young-Ran; Kim, SuYeon; Park, Young Ho; Park, So Young; Kim, SangYun

    2015-01-01

    Although Korea had a national surveillance system for Creutzfeldt-Jakob disease (CJD), it was mainly dependent on attending physician's reports. Thus, little prospective data about the epidemiology, characteristics, and final diagnoses of suspected patients were available. We have established a nationwide network for the active surveillance of patients with suspected CJD. When the requested cerebrospinal fluid (CSF) samples tested positive for 14-3-3 protein, we investigated the clinical characteristics of the corresponding patients and followed them until their final diagnoses were confirmed. A total of 218 samples were requested for CSF assays from May 2010 to August 2012, and 106 (48.6%) were positive for 14-3-3 protein. In 89 patients with complete clinical data, 38 (42.7%) were diagnosed with probable CJD and the estimated annual occurrence of CJD was 16.3 persons-per-year. The most common diagnoses of the remainder were central nervous system infection and any-cause encephalopathy. Non-CJD subjects showed worse initial consciousness levels than CJD patients. This preliminary study showed that the number of reported cases of CJD and the true positivity rates of CSF 14-3-3 protein assays were both low in Korea. An active surveillance system is urgently needed to provide the latest nationwide epidemiological data of CJD.

  19. Familial Creutzfeldt-Jakob disease with the E200K mutation: longitudinal neuroimaging from asymptomatic to symptomatic CJD.

    PubMed

    Cohen, Oren S; Chapman, Joab; Korczyn, Amos D; Nitsan, Zeev; Appel, Shmuel; Hoffmann, Chen; Rosenmann, Hanna; Kahana, Esther; Lee, Hedok

    2015-03-01

    Familial Creutzfeldt-Jakob disease (fCJD) in Jews of Libyan ancestry is caused by an E200K mutation in the PRNP gene. While carriers are born with this mutation, they usually remain asymptomatic until middle age. Early detection of conversion is crucial for understanding and eventually for the treatment of the disease. The aim of this study was to report longitudinal MRI data in E200K individuals who eventually converted from healthy mutation carriers to clinically symptomatic CJD. As a part of a prospective study, asymptomatic E200K mutation carriers were scanned annually until their conversion to symptomatic disease. Standardized diffusion and anatomical MR sequences were performed before and after clinical conversion in the subjects and those were compared to 15 non-carrier siblings ("healthy controls"). Blinded radiological readings and region of interest analyses were performed. Radiological readings of individual cases failed to detect characteristic changes in the scans taken before the conversion. Region of interest analysis of diffusion changes in pre-symptomatic stage was inconclusive; however, ADC reduction was found in early and late stages of the disease. Computerized volumetric analysis revealed monotonic volume reductions in thalamus, putamen and caudate following conversion, and the lateral ventricles showed dilatation of up to 62 % after clinical conversion. Although the clinical manifestations at disease onset are variable, the diffusion abnormalities and/or volume changes in the thalamus and basal ganglia during conversion may indicate early involvement of the thalamostriatal neuronal circuit.

  20. An alarming presentation of Creutzfeldt-Jakob disease following a self-inflicted gunshot wound to the head.

    PubMed

    Harnish, Carissa; Gross, Brian; Rittenhouse, Katelyn; Bupp, Katherine; Vellucci, Ashley; Anderson, Jeffrey; Riley, Deborah; Rogers, Frederick B

    2015-05-01

    Transmissible spongiform encephalopathies (TSE), also known as prion diseases, are characterized by rapid and fatal neurological decline. They not only detrimentally affect the patient, but also present additional challenges to healthcare systems due to the infectivity of the tissues and the difficulty of inactivating the prion. The most common TSE is Creutzfeldt-Jakob disease (CJD), which can occur after familial, spontaneous or acquired transmission. TSEs received more attention after the development of variant CJD (vCJD), also known as Mad Cow Disease, in the UK during the mid-1990s. Unlike familial or spontaneous CJD, this variant was connected to consumption of cattle contaminated with the prion disease, bovine spongiform encephalopathy.This development increased interest in the etiology of CJD and other TSEs and the risk it presents as an infectious disease. The following details the case of a 59-year-old male infected with CJD presented to our level II trauma center for treatment following a self-inflicted gunshot wound to the head.

  1. Mutation and polymorphism of the prion protein gene in Libyan Jews with Creutzfeldt-Jakob disease (CJD)

    SciTech Connect

    Gabizon, R.; Rosenmann, H.; Meiner, Z.; Kahana, I. ); Kahana, E. ); Shugart, Y.; Ott, J. ); Prusiner, S.B. )

    1993-10-01

    The inherited prion diseases are neurodegenerative disorders which are not only genetic but also transmissible. More than a dozen mutations in the prion protein gene that result in nonconservative amino acid substitutions segregate with the inherited prion diseases including familial Creutzfeldt-Jakob disease (CJD). In Israel, the incidence of CJD is about 1 case/10[sup 4] Libyan Jews. A Lys[sub 200] substitution segregates with CJD and is reported here to be genetically linked to CJD with a lod score of >4.8. Some healthy elderly Lys[sub 200] carriers > age 65 years were identified, suggesting the possibility of incomplete penetrance. In contrast, no linkage was found between the development of familial CJD and a polymorphism encoding either Met[sub 129] or Val[sub 129]. All Libyan Jewish CJD patients with the Lys[sub 200] mutation encode a Met[sub 129] on the mutant allele. Homozygosity for Met[sub 129] did not correlate with age at disease onset or the duration of illness. The frequency of the Met[sub 129] allele was higher in the affected pedigrees than in a control population of Libyan Jews. The frequency of the Met[sub 129] and Val[sub 129] alleles in the control Libyan population was similar to that found in the general Caucasian population. The identification of three Libyan Jews homozygous for the Lys[sub 200] mutation suggests frequent intrafamilial marriages, a custom documented by genealogical investigations. 26 refs., 3 figs., 6 tabs.

  2. Immunohistochemical confirmation of Creutzfeldt-Jakob disease with a long clinical course with amyloid plaque core antibodies.

    PubMed Central

    Kitamoto, T.; Tateishi, J.

    1988-01-01

    Amyloid plaques have been found in the brains of some patients with Creutzfeldt-Jakob disease (CJD) and all patients with Gerstmann-Sträussler syndrome (GSS). We examined paraffin sections from 45 patients with CJD or GSS and from 51 patients with other neurologic diseases, using an antiserum against GSS amyloid plaque cores. The GSS amyloid plaque core antiserum revealed not only birefringent amyloid plaques but also small plaques that cannot be detected by the staining with Congo red dye. Positive immunolabeling was demonstrated in 59% of 34 Japanese patients with CJD, in 100% of 11 patients with GSS, and in none with other neurologic diseases. All cases of CJD of short duration (less than 11 months) were evaluated as being negative, and 95% of 21 long survivors (over 12 months) were positive. This immunohistochemical approach revealed that amyloid plaque is a hallmark of CJD with a long clinical course. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:3289400

  3. The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt-Jakob disease and scrapie agents.

    PubMed

    Manuelidis, Laura; Chakrabarty, Trisha; Miyazawa, Kohtaro; Nduom, Nana-Aba; Emmerling, Kaitlin

    2009-08-11

    Human sporadic Creutzfeldt-Jakob disease (sCJD), endemic sheep scrapie, and epidemic bovine spongiform encephalopathy (BSE) are caused by a related group of infectious agents. The new U.K. BSE agent spread to many species, including humans, and clarifying the origin, specificity, virulence, and diversity of these agents is critical, particularly because infected humans do not develop disease for many years. As with viruses, transmissible spongiform encephalopathy (TSE) agents can adapt to new species and become more virulent yet maintain fundamentally unique and stable identities. To make agent differences manifest, one must keep the host genotype constant. Many TSE agents have revealed their independent identities in normal mice. We transmitted primate kuru, a TSE once epidemic in New Guinea, to mice expressing normal and approximately 8-fold higher levels of murine prion protein (PrP). High levels of murine PrP did not prevent infection but instead shortened incubation time, as would be expected for a viral receptor. Sporadic CJD and BSE agents and representative scrapie agents were clearly different from kuru in incubation time, brain neuropathology, and lymphoreticular involvement. Many TSE agents can infect monotypic cultured GT1 cells, and unlike sporadic CJD isolates, kuru rapidly and stably infected these cells. The geographic independence of the kuru agent provides additional reasons to explore causal environmental pathogens in these infectious neurodegenerative diseases.

  4. MM2-thalamic Creutzfeldt-Jakob disease: neuropathological, biochemical and transmission studies identify a distinctive prion strain.

    PubMed

    Moda, Fabio; Suardi, Silvia; Di Fede, Giuseppe; Indaco, Antonio; Limido, Lucia; Vimercati, Chiara; Ruggerone, Margherita; Campagnani, Ilaria; Langeveld, Jan; Terruzzi, Alessandro; Brambilla, Antonio; Zerbi, Pietro; Fociani, Paolo; Bishop, Matthew T; Will, Robert G; Manson, Jean C; Giaccone, Giorgio; Tagliavini, Fabrizio

    2012-09-01

    In Creutzfeldt-Jakob disease (CJD), molecular typing based on the size of the protease resistant core of the disease-associated prion protein (PrP(Sc) ) and the M/V polymorphism at codon 129 of the PRNP gene correlates with the clinico-pathologic subtypes. Approximately 95% of the sporadic 129MM CJD patients are characterized by cerebral deposition of type 1 PrP(Sc) and correspond to the classic clinical CJD phenotype. The rare 129MM CJD patients with type 2 PrP(Sc) are further subdivided in a cortical and a thalamic form also indicated as sporadic fatal insomnia. We observed two young patients with MM2-thalamic CJD. Main neuropathological features were diffuse, synaptic PrP immunoreactivity in the cerebral cortex and severe neuronal loss and gliosis in the thalamus and olivary nucleus. Western blot analysis showed the presence of type 2A PrP(Sc) . Challenge of transgenic mice expressing 129MM human PrP showed that MM2-thalamic sporadic CJD (sCJD) was able to transmit the disease, at variance with MM2-cortical sCJD. The affected mice showed deposition of type 2A PrP(Sc) , a scenario that is unprecedented in this mouse line. These data indicate that MM2-thalamic sCJD is caused by a prion strain distinct from the other sCJD subtypes including the MM2-cortical form.

  5. Variant Creutzfeldt-Jakob disease: prion protein genotype analysis of positive appendix tissue samples from a retrospective prevalence study.

    PubMed

    Ironside, James W; Bishop, Matthew T; Connolly, Kelly; Hegazy, Doha; Lowrie, Suzanne; Le Grice, Margaret; Ritchie, Diane L; McCardle, Linda M; Hilton, David A

    2006-05-20

    To perform prion protein gene (PRNP) codon 129 analysis in DNA extracted from appendix tissue samples that had tested positive for disease associated prion protein. Reanalysis of positive cases identified in a retrospective anonymised unlinked prevalence study of variant Creutzfeldt-Jakob disease (vCJD) in the United Kingdom. Three positive appendix tissue samples out of 12,674 samples of appendix and tonsil tested for disease associated prion protein. The patients from whom these samples were obtained were aged 20-29 years at the time of surgery, which took place in 1996-9. Pathology departments in two tertiary centres in England and Scotland. Adequate DNA was available for analysis in two of the three specimens, both of which were homozygous for valine at codon 129 in the PRNP. This is the first indication that the valine homozygous subgroup at codon 129 in the PRNP is susceptible to vCJD infection. All tested clinical cases of vCJD have so far occurred in the methionine homozygous subgroup, and a single case of probable iatrogenic vCJD infection has been identified in one patient who was a methionine/valine heterozygote at this genetic locus. People infected with vCJD with a valine homozygous codon 129 PRNP genotype may have a prolonged incubation period, during which horizontal spread of the infection could occur either from blood donations or from contaminated surgical instruments used on these individuals during the asymptomatic phase of the illness.

  6. Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene

    SciTech Connect

    Goldfarb, L.G.; Brown, P.; McCombie, W.R.; Gibbs, C.J. Jr.; Gajdusek, D.C. ); Goldgaber, D. ); Swergold, G.D. ); Wills, P.R. ); Cervenakova, L. ); Baron, H. )

    1991-12-01

    The PRNP gene, encoding the amyloid precursor protein that is centrally involved in Creutzfeldt-Jakob disease (CJD), has an unstable region of five variant tandem octapeptide coding repeats between codons 51 and 91. The authors screened a total of 535 individuals for the presence of extra repeats in this region, including patients with sporadic and familial forms of spongiform encephalopathy, members of their families, other neurological and non-neurological patients, and normal controls. They identified three CJD families (in each of which the proband's disease was neuropathologically confirmed and experimentally transmitted to primates) that were heterozygous for alleles with 10, 12, or 13 repeats, some of which had wobble nucleotide substitutions. They also found one individual with 9 repeats and no nucleotide substitutions who had no evidence of neurological disease. These observations, together with data on published British patients with 11 and 14 repeats, strongly suggest that the occurrence of 10 or more octapeptide repeats in the encoded amyloid precursor protein predisposes to CJD.

  7. Immune responses in rapidly progressive dementia: a comparative study of neuroinflammatory markers in Creutzfeldt-Jakob disease, Alzheimer's disease and multiple sclerosis.

    PubMed

    Stoeck, Katharina; Schmitz, Matthias; Ebert, Elisabeth; Schmidt, Christian; Zerr, Inga

    2014-10-15

    Immunological responses may contribute to disease progression and clinical heterogeneity in neurodegenerative dementia, for example, Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD). Recently, a rapidly progressive form of AD (rpAD) has been described. On neuropathological grounds classical AD and rpAD are not distinguishable at present. All those protein aggregopathies show a state of chronic inflammation with microglia activation and production of proinflammatory cytokines. In this context, it is hypothesized that the severity of the surrounding inflammation substantially contributes to disease progression and accelerated disease courses as seen in rpAD.

  8. Spreading brain lesions in a familial Creutzfeldt-Jakob disease with V180I mutation over 4 years

    PubMed Central

    2012-01-01

    Background We report a female patient with familial Creutzfeldt-Jakob disease with V180I mutation (fCJD with V180I), who was serially followed up with magnetic resonance imaging (MRI) and electroencephalogram (EEG) for up to four years. Case presentation At 6 months after the onset, diffusion-weighted images (DWI) and fluid-attenuated inversion recovery (FLAIR) of brain MRI revealed an increased signal intensity in the bilateral frontal, temporal, and parietal cerebral cortex with left dominancy except for the occipital lobe. However, her follow-up MRI at four years showed the high-signal regions spreading to the occipital cerebral cortex in DWI and FLAIR images, and bilateral frontal cerebral white matter in FLAIR images. EEG showed a progressive and general slow high-voltage rhythm from 7–8 to 3–5 c/s over four years, without evidence of periodic synchronous discharge. These findings correspond to the symptom progression even after akinetic mutism at 18 months. Conclusion We suggest that serial MRI and EEG examinations are useful for early diagnosis of fCJD with V180I and for monitoring disease progression. PMID:23176099

  9. Spreading brain lesions in a familial Creutzfeldt-Jakob disease with V180I mutation over 4 years.

    PubMed

    Deguchi, Kentaro; Takamiya, Motonori; Deguchi, Shoko; Morimoto, Nobutoshi; Kurata, Tomoko; Ikeda, Yoshio; Abe, Koji

    2012-11-24

    We report a female patient with familial Creutzfeldt-Jakob disease with V180I mutation (fCJD with V180I), who was serially followed up with magnetic resonance imaging (MRI) and electroencephalogram (EEG) for up to four years. At 6 months after the onset, diffusion-weighted images (DWI) and fluid-attenuated inversion recovery (FLAIR) of brain MRI revealed an increased signal intensity in the bilateral frontal, temporal, and parietal cerebral cortex with left dominancy except for the occipital lobe. However, her follow-up MRI at four years showed the high-signal regions spreading to the occipital cerebral cortex in DWI and FLAIR images, and bilateral frontal cerebral white matter in FLAIR images. EEG showed a progressive and general slow high-voltage rhythm from 7-8 to 3-5 c/s over four years, without evidence of periodic synchronous discharge. These findings correspond to the symptom progression even after akinetic mutism at 18 months. We suggest that serial MRI and EEG examinations are useful for early diagnosis of fCJD with V180I and for monitoring disease progression.

  10. Clinical and MRI evaluation of anxiety as the first symptom of sporadic Creutzfeldt-Jakob disease: A case report

    PubMed Central

    LIU, WEIBO; LU, YUNRONG; ZHONG, GUODONG; JIANG, BIAO; PAN, ZHIJIE

    2016-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare, transmissible prion disease of the brain, characterized by prominent neurological symptoms and progressive dementia. Early psychiatric manifestations as an initial or sole symptom of sCJD are relatively rare. The current report describes an elderly female patient with sCJD demonstrating anxiety as an initial symptom. The present patient was initially diagnosed with adjustment disorder and anxiety; however, the rapid deterioration of the patient's cognitive and neurological functioning led to a diagnosis of sCJD. Diffusion-weighted magnetic resonance images of the brain supported a diagnosis of sCJD, and it was posited that the abnormalities of gray matter that were observed within the bilateral cingulate cortex may be the pathophysiological basis of the anxiety associated with this case of sCJD. The patient eventually succumbed to inhalational bronchopneumonia 5 months after anxiety onset. The present case report emphasizes the importance of secondary causes of anxiety symptoms in elderly patients, and indicates that brain DWI is a non-invasive and useful examination in the early diagnosis of sCJD. PMID:27073474

  11. The role of stress and anxiety in the onset of familial Creutzfeldt-Jakob Disease (CJD): review.

    PubMed

    Gigi, Ariela

    2009-09-01

    Creutzfeldt-Jakob Disease (CJD) is considered to be a sudden and fatal degenerative brain disorder that leads to death within a few months. In the last decade, we have studied the course of familial CJD (fCJD) among Jews of Libyan descent, one of the largest clusters of fCJD in the world. Recently, we published results that included the identification of abnormal anxiety levels in healthy CJD E200K mutation carriers that were significantly different from those of healthy non-carriers from the same families. All participants were first-degree relatives of patients known to have been carriers of the E200K mutation and had died from CJD, and none of the participants was aware of his/her genetic make-up. In the current review, it is suggested that an abnormality in anxiety levels among the healthy fCJD mutation carriers may reflect the clinical presentation of the disease onset especially during and after any stressful experience. This hypothesis is supported by a summary of relevant literature, dealing with psychological, physiological, and cellular aspects.

  12. Protective Effect of Val129-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease

    PubMed Central

    Fernández-Borges, Natalia; Espinosa, Juan Carlos; Marín-Moreno, Alba; Aguilar-Calvo, Patricia; Asante, Emmanuel A.; Kitamoto, Tetsuyuki; Mohri, Shirou; Andréoletti, Olivier

    2017-01-01

    Bovine spongiform encephalopathy (BSE) is the only known zoonotic prion that causes variant Creutzfeldt-Jakob disease (vCJD) in humans. The major risk determinant for this disease is the polymorphic codon 129 of the human prion protein (Hu-PrP), where either methionine (Met129) or valine (Val129) can be encoded. To date, all clinical and neuropathologically confirmed vCJD cases have been Met129 homozygous, with the exception of 1 recently reported Met/Val heterozygous case. Here, we found that transgenic mice homozygous for Val129 Hu-PrP show severely restricted propagation of the BSE prion strain, but this constraint can be partially overcome by adaptation of the BSE agent to the Met129 Hu-PrP. In addition, the transmission of vCJD to transgenic mice homozygous for Val129 Hu-PrP resulted in a prion with distinct strain features. These observations may indicate increased risk for vCJD secondary transmission in Val129 Hu-PrP–positive humans with the emergence of new strain features. PMID:28820136

  13. Altered Mitochondria, Protein Synthesis Machinery, and Purine Metabolism Are Molecular Contributors to the Pathogenesis of Creutzfeldt-Jakob Disease.

    PubMed

    Ansoleaga, Belén; Garcia-Esparcia, Paula; Llorens, Franc; Hernández-Ortega, Karina; Carmona Tech, Margarita; Antonio Del Rio, José; Zerr, Inga; Ferrer, Isidro

    2016-06-12

    Neuron loss, synaptic decline, and spongiform change are the hallmarks of sporadic Creutzfeldt-Jakob disease (sCJD), and may be related to deficiencies in mitochondria, energy metabolism, and protein synthesis. To investigate these relationships, we determined the expression levels of genes encoding subunits of the 5 protein complexes of the electron transport chain, proteins involved in energy metabolism, nucleolar and ribosomal proteins, and enzymes of purine metabolism in frontal cortex samples from 15 cases of sCJD MM1 and age-matched controls. We also assessed the protein expression levels of subunits of the respiratory chain, initiation and elongation translation factors of protein synthesis, and localization of selected mitochondrial components. We identified marked, generalized alterations of mRNA and protein expression of most subunits of all 5 mitochondrial respiratory chain complexes in sCJD cases. Expression of molecules involved in protein synthesis and purine metabolism were also altered in sCJD. These findings point to altered mRNA and protein expression of components of mitochondria, protein synthesis machinery, and purine metabolism as components of the pathogenesis of CJD. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

  14. Universal white blood cell reduction in Europe: has transmission of variant Creutzfeldt-Jakob disease been prevented?

    PubMed

    Vamvakas, Eleftherios C

    2011-04-01

    Universal white blood cell (WBC) reduction was introduced in Europe to prevent transmission of variant Creutzfeldt-Jakob disease (vCJD) by transfusion. Findings from rodent models indicate that WBC reduction should not prevent vCJD transmission because the residual plasma infectivity suffices to infect transfusion recipients even under optimistic infectivity assumptions. Although infectivity in human blood may not partition in the manner in which it is distributed in rodents, prion-reduction filters remove the residual plasma infectivity in rodent models. Precautionary introduction of prion filtration in the UK--for patients without dietary exposure to bovine spongiform encephalopathy and in the absence of a reported case of vCJD transmission attributable to infectivity residing in plasma--is consistent with the (already in place for such subjects) precautionary importation to the UK of fresh frozen plasma from low-risk countries. Thus, implementation of prion filtration in the UK does not imply that universal WBC reduction--as currently practiced in Europe--does not abrogate transmission of vCJD. Because neither a human case of vCJD transmission through transfusion of WBC-reduced red blood cells nor a case of experimental bovine spongiform encephalopathy transmission by WBC-reduced transfusion to sheep has been reported, it cannot be concluded that ordinary WBC reduction is ineffective in preventing transfusion transmission in humans. Accordingly, universal WBC reduction for the prevention of vCJD in Europe should continue.

  15. Sporadic Creutzfeldt-Jakob Disease MM1+2C and MM1 are Identical in Transmission Properties.

    PubMed

    Kobayashi, Atsushi; Matsuura, Yuichi; Iwaki, Toru; Iwasaki, Yasushi; Yoshida, Mari; Takahashi, Hitoshi; Murayama, Shigeo; Takao, Masaki; Kato, Shinsuke; Yamada, Masahito; Mohri, Shirou; Kitamoto, Tetsuyuki

    2016-01-01

    The genotype (methionine, M or valine, V) at polymorphic codon 129 of the PRNP gene and the type (1 or 2) of abnormal prion protein in the brain are the major determinants of the clinicopathological features of sporadic Creutzfeldt-Jakob disease (CJD), thus providing molecular basis for classification of sporadic CJD, that is, MM1, MM2, MV1, MV2, VV1 or VV2. In addition to these "pure" cases, "mixed" cases presenting mixed neuropathological and biochemical features have also been recognized. The most frequently observed mixed form is the co-occurrence of MM1 and MM2, namely MM1+2. However, it has remained elusive whether MM1+2 could be a causative origin of dura mater graft-associated CJD (dCJD), one of the largest subgroups of iatrogenic CJD. To test this possibility, we performed transmission experiments of MM1+2 prions and a systematic neuropathological examination of dCJD patients in the present study. The transmission properties of the MM1+2 prions were identical to those of MM1 prions because MM2 prions lacked transmissibility. In addition, the neuropathological characteristics of MM2 were totally absent in dCJD patients examined. These results suggest that MM1+2 can be a causative origin of dCJD and causes neuropathological phenotype similar to that of MM1.

  16. Sporadic Creutzfeldt-Jakob Disease: Prion Pathology in Medulla Oblongata-Possible Routes of Infection and Host Susceptibility.

    PubMed

    Iacono, Diego; Ferrari, Sergio; Gelati, Matteo; Zanusso, Gianluigi; Mariotto, Sara; Monaco, Salvatore

    2015-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disorder, is characterized by remarkable phenotypic variability, which is influenced by the conformation of the pathologic prion protein and the methionine/valine polymorphic codon 129 of the prion protein gene. While the etiology of sCJD remains unknown, it has been hypothesized that environmental exposure to prions might occur through conjunctival/mucosal contact, oral ingestion, inhalation, or simultaneous involvement of the olfactory and enteric systems. We studied 21 subjects with definite sCJD to assess neuropathological involvement of the dorsal motor nucleus of the vagus and other medullary nuclei and to evaluate possible associations with codon 129 genotype and prion protein conformation. The present data show that prion protein deposition was detected in medullary nuclei of distinct sCJD subtypes, either valine homozygous or heterozygous at codon 129. These findings suggest that an "environmental exposure" might occur, supporting the hypothesis that external sources of contamination could contribute to sCJD in susceptible hosts. Furthermore, these novel data could shed the light on possible causes of sCJD through a "triple match" hypothesis that identify environmental exposure, host genotype, and direct exposure of specific anatomical regions as possible pathogenetic factors.

  17. Notifying patients exposed to blood products associated with Creutzfeldt-Jakob disease: integrating science, legal duties and ethical mandates

    PubMed Central

    Caulfield, T; Dossetor, J; Boshkov, L; Hannon, J; Sawyer, D; Robertson, G

    1997-01-01

    The issue of notifying people who have been exposed to blood products that have been associated with Creutzfeldt-Jakob disease (CJD) has arisen at a time when the Canadian blood system is under intense scrutiny. As a result, the Canadian Red Cross Society issued a recommendation to health care institutions that recipients of CJD-associated blood products be identified, notified and counselled. Although Canadian jurisprudence in the realm of informed consent may support a policy of individual notification, a review of the scientific evidence and the applicable ethical principles arguably favours a policy of a more general public notification. Indeed, situations such as this require a unique approach to the formation of legal and ethical duties, one that effectively integrates all relevant factors. As such, the authors argue that individual notification is currently not justified. Nevertheless, if a system of general notification is implemented (e.g., through a series of public health announcements), it should provide, for people who wish to know, the opportunity to find out whether they were given CJD-associated products. PMID:9371070

  18. Deep Learning Representation from Electroencephalography of Early-Stage Creutzfeldt-Jakob Disease and Features for Differentiation from Rapidly Progressive Dementia.

    PubMed

    Morabito, Francesco Carlo; Campolo, Maurizio; Mammone, Nadia; Versaci, Mario; Franceschetti, Silvana; Tagliavini, Fabrizio; Sofia, Vito; Fatuzzo, Daniela; Gambardella, Antonio; Labate, Angelo; Mumoli, Laura; Tripodi, Giovanbattista Gaspare; Gasparini, Sara; Cianci, Vittoria; Sueri, Chiara; Ferlazzo, Edoardo; Aguglia, Umberto

    2017-03-01

    A novel technique of quantitative EEG for differentiating patients with early-stage Creutzfeldt-Jakob disease (CJD) from other forms of rapidly progressive dementia (RPD) is proposed. The discrimination is based on the extraction of suitable features from the time-frequency representation of the EEG signals through continuous wavelet transform (CWT). An average measure of complexity of the EEG signal obtained by permutation entropy (PE) is also included. The dimensionality of the feature space is reduced through a multilayer processing system based on the recently emerged deep learning (DL) concept. The DL processor includes a stacked auto-encoder, trained by unsupervised learning techniques, and a classifier whose parameters are determined in a supervised way by associating the known category labels to the reduced vector of high-level features generated by the previous processing blocks. The supervised learning step is carried out by using either support vector machines (SVM) or multilayer neural networks (MLP-NN). A subset of EEG from patients suffering from Alzheimer's Disease (AD) and healthy controls (HC) is considered for differentiating CJD patients. When fine-tuning the parameters of the global processing system by a supervised learning procedure, the proposed system is able to achieve an average accuracy of 89%, an average sensitivity of 92%, and an average specificity of 89% in differentiating CJD from RPD. Similar results are obtained for CJD versus AD and CJD versus HC.

  19. Genomic Characteristics of Genetic Creutzfeldt-Jakob Disease Patients with V180I Mutation and Associations with Other Neurodegenerative Disorders

    PubMed Central

    Lee, Sol Moe; Chung, Myungguen; Hyeon, Jae Wook; Jeong, Seok Won; Ju, Young Ran; Kim, Heebal; Lee, Jeongmin; Kim, SangYun; An, Seong Soo A.; Cho, Sung Beom; Lee, Yeong Seon; Kim, Su Yeon

    2016-01-01

    Inherited prion diseases (IPDs), including genetic Creutzfeldt-Jakob disease (gCJD), account for 10–15% of cases of prion diseases and are associated with several pathogenic mutations, including P102L, V180I, and E200K, in the prion protein gene (PRNP). The valine to isoleucine substitution at codon 180 (V180I) of PRNP is the most common pathogenic mutation causing gCJD in East Asian patients. In this study, we conducted follow-up analyses to identify candidate factors and their associations with disease onset. Whole-genome sequencing (WGS) data of five gCJD patients with V180I mutation and 145 healthy individuals were used to identify genomic differences. A total of 18,648,850 candidate variants were observed in only the patient group, 29 of them were validated as variants. Four of these validated variants were nonsense mutations, six were observed in genes directly or indirectly related to neurodegenerative disorders (NDs), such as LPA, LRRK2, and FGF20. More than half of validated variants were categorized in Gene Ontology (GO) terms of binding and/or catalytic activity. Moreover, we found differential genome variants in gCJD patients with V180I mutation, including one uniquely surviving 10 years after diagnosis of the disease. Elucidation of the relationships between gCJD and Alzheimer’s disease or Parkinson’s disease at the genomic level will facilitate further advances in our understanding of the specific mechanisms mediating the pathogenesis of NDs and gold standard therapies for NDs. PMID:27341347

  20. Alzheimer-type neuropathology in a 28 year old patient with iatrogenic Creutzfeldt-Jakob disease after dural grafting.

    PubMed

    Preusser, M; Ströbel, T; Gelpi, E; Eiler, M; Broessner, G; Schmutzhard, E; Budka, H

    2006-03-01

    We report the case of a 28 year old man who had received a cadaverous dura mater graft after a traumatic open skull fracture with tearing of the dura at the age of 5 years. A clinical suspicion of Creutzfeldt-Jakob disease (CJD) was confirmed by a brain biopsy 5 months prior to death and by autopsy, thus warranting the diagnosis of iatrogenic CJD (iCJD) according to WHO criteria. Immunohistochemistry showed widespread cortical depositions of disease associated prion protein (PrP(sc)) in a synaptic pattern, and western blot analysis identified PrP(sc) of type 2A according to Parchi et al. Surprisingly, we found Alzheimer-type senile plaques and cerebral amyloid angiopathy in widespread areas of the brain. Plaque-type and vascular amyloid was immunohistochemically identified as deposits of beta-A4 peptide. CERAD criteria for diagnosis of definite Alzheimer's disease (AD) were met in the absence of neurofibrillar tangles or alpha-synuclein immunoreactive inclusions. There was no family history of AD, CJD, or any other neurological disease, and genetic analysis showed no disease specific mutations of the prion protein, presenilin 1 and 2, or amyloid precursor protein genes. This case represents (a) the iCJD case with the longest incubation time after dural grafting reported so far, (b) the youngest documented patient with concomitant CJD and Alzheimer-type neuropathology to date, (c) the first description of Alzheimer-type changes in iCJD, and (d) the second case of iCJD in Austria. Despite the young patient age, the Alzheimer-type changes may be an incidental finding, possibly related to the childhood trauma.

  1. Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings

    PubMed Central

    Baiardi, Simone; Capellari, Sabina; Ladogana, Anna; Strumia, Silvia; Santangelo, Mario; Pocchiari, Maurizio; Parchi, Piero

    2015-01-01

    The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical disease, a high prevalence of periodic sharp-wave complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of “probable” CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2). PMID:26682685

  2. Prion Protein-Hemin Interaction Upregulates Hemoglobin Synthesis: Implications for Cerebral Hemorrhage and Sporadic Creutzfeldt-Jakob Disease.

    PubMed

    Tripathi, Ajai K; Singh, Neena

    2016-01-01

    Hemin is known to induce endocytosis of prion-protein (PrP(C)) from the neuronal plasma membrane, potentially limiting propagation of the disease causing PrP-scrapie (PrP(Sc)) isoform. Hemin is therefore an attractive disease-modifying option for sporadic Creutzfeldt-Jakob disease (sCJD), a human prion disorder with no effective treatment. The hemin-PrP(C) interaction is also of interest in cerebral-hemorrhage (CH), a condition where potentially toxic hemin molecules come in contact with neuronal PrP(C). Interestingly, PrP(C) is upregulated in penumbric neurons surrounding CH and is known to confer neuroprotection in a dose-dependent manner. The underlying mechanism, however, is not clear. Here, we report that hemin binds PrP(C) on diverse cell lines, resulting in its aggregation or degradation in a cell-type specific manner. Surprisingly, the hemin-PrP(C) interaction upregulates Hb synthesis in hematopoietic cells, a response reversed by deleting the hemin-binding octa-peptide repeat region of PrP(C). A similar response is noted in brain organotypic cultures where exposure to hemin induces significantly more α-globin in wild-type (PrP(+/+)) relative to PrP-knock-out (PrP(-/-)) samples. Furthermore, red blood cells and brain tissue from PrP(-/-) mice show significantly less α-globin relative to PrP(+/+) controls, indicating a positive effect of PrP(C) on Hb synthesis under physiological conditions as well. Surprisingly, levels of α-globin are significantly higher in sCJD brain tissue relative to controls, suggesting compensatory upregulation of Hb synthesis by surviving neurons or misregulation in diseased brains. These observations reveal a unique function of PrP(C) that is likely to impact the therapeutic management of CH and sCJD.

  3. Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings.

    PubMed

    Baiardi, Simone; Capellari, Sabina; Ladogana, Anna; Strumia, Silvia; Santangelo, Mario; Pocchiari, Maurizio; Parchi, Piero

    2016-01-01

    The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical disease, a high prevalence of periodic sharp-wave complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of "probable" CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2).

  4. Sporadic Creutzfeldt-Jakob disease diagnostic accuracy is improved by a new CSF ELISA 14-3-3γ assay.

    PubMed

    Leitão, M J; Baldeiras, I; Almeida, M R; Ribeiro, M H; Santos, A C; Ribeiro, M; Tomás, J; Rocha, S; Santana, I; Oliveira, C R

    2016-05-13

    Protein 14-3-3 is a reliable marker of rapid neuronal damage, specifically increased in cerebrospinal fluid (CSF) of sporadic Creutzfeldt-Jakob disease (sCJD) patients. Its detection is usually performed by Western Blot (WB), prone to methodological issues. Our aim was to evaluate the diagnostic performance of a recently developed quantitative enzyme-linked immunosorbent (ELISA) assay for 14-3-3γ, in comparison with WB and other neurodegeneration markers. CSF samples from 145 patients with suspicion of prion disease, later classified as definite sCJD (n=72) or Non-prion diseases (Non-CJD; n=73) comprised our population. 14-3-3 protein was determined by WB and ELISA. Total Tau (t-Tau) and phosphorylated Tau (p-Tau) were also evaluated. Apolipoprotein E gene (ApoE) and prionic protein gene (PRNP) genotyping was assessed. ELISA 14-3-3γ levels were significantly increased in sCJD compared to Non-CJD patients (p<0.001), showing very good accuracy (AUC=0.982; sensitivity=97%; specificity=94%), and matching WB results in 81% of all cases. It strongly correlated with t-Tau and p-Tau (p<0.0001), showing slightly higher specificity (14-3-3 WB - 63%; Tau - 90%; p-Tau/t-Tau ratio - 88%). From WB inconclusive results (n=44), ELISA 14-3-3γ correctly classified 41 patients. Additionally, logistic regression analysis selected ELISA 14-3-3γ as the best single predictive marker for sCJD (overall accuracy=93%). ApoE and PRNP genotypes did not influence ELISA 14-3-3γ levels. Despite specificity for 14-3-3γ isoform, ELISA results not only match WB evaluation but also help discrimination of inconclusive results. Our results therefore reinforce this assay as a single screening test, allowing higher sample throughput and unequivocal results.

  5. Risk Assessment of Transmission of Sporadic Creutzfeldt-Jakob Disease in Endodontic Practice in Absence of Adequate Prion Inactivation

    PubMed Central

    Bourvis, Nadège; Boelle, Pierre-Yves; Cesbron, Jean-Yves; Valleron, Alain-Jacques

    2007-01-01

    Background Experimental results evidenced the infectious potential of the dental pulp of animals infected with transmissible spongiform encephalopathies (TSE). This route of iatrogenic transmission of sporadic Creutzfeldt-Jakob disease (sCJD) may exist in humans via reused endodontic instruments if inadequate prion decontamination procedures are used. Methodology/Principal Findings To assess this risk, 10 critical parameters in the transmission process were identified, starting with contamination of an endodontic file during treatment of an infectious sCJD patient and ending with possible infection of a subsequent susceptible patient. It was assumed that a dose-risk response existed, with no-risk below threshold values. Plausible ranges of those parameters were obtained through literature search and expert opinions, and a sensitivity analysis was conducted. Without effective prion-deactivation procedures, the risk of being infected during endodontic treatment ranged between 3.4 and 13 per million procedures. The probability that more than one case was infected secondary to endodontic treatment of an infected sCJD patient ranged from 47% to 77% depending on the assumed quantity of infective material necessary for disease transmission. If current official recommendations on endodontic instrument decontamination were strictly followed, the risk of secondary infection would become quasi-null. Conclusion The risk of sCJD transmission through endodontic procedure compares with other health care risks of current concern such as death after liver biopsy or during general anaesthesia. These results show that single instrument use or adequate prion-decontamination procedures like those recently implemented in dental practice must be rigorously enforced. PMID:18159228

  6. Risk assessment of transmission of sporadic Creutzfeldt-Jakob disease in endodontic practice in absence of adequate prion inactivation.

    PubMed

    Bourvis, Nadège; Boelle, Pierre-Yves; Cesbron, Jean-Yves; Valleron, Alain-Jacques

    2007-12-26

    Experimental results evidenced the infectious potential of the dental pulp of animals infected with transmissible spongiform encephalopathies (TSE). This route of iatrogenic transmission of sporadic Creutzfeldt-Jakob disease (sCJD) may exist in humans via reused endodontic instruments if inadequate prion decontamination procedures are used. To assess this risk, 10 critical parameters in the transmission process were identified, starting with contamination of an endodontic file during treatment of an infectious sCJD patient and ending with possible infection of a subsequent susceptible patient. It was assumed that a dose-risk response existed, with no-risk below threshold values. Plausible ranges of those parameters were obtained through literature search and expert opinions, and a sensitivity analysis was conducted. Without effective prion-deactivation procedures, the risk of being infected during endodontic treatment ranged between 3.4 and 13 per million procedures. The probability that more than one case was infected secondary to endodontic treatment of an infected sCJD patient ranged from 47% to 77% depending on the assumed quantity of infective material necessary for disease transmission. If current official recommendations on endodontic instrument decontamination were strictly followed, the risk of secondary infection would become quasi-null. The risk of sCJD transmission through endodontic procedure compares with other health care risks of current concern such as death after liver biopsy or during general anaesthesia. These results show that single instrument use or adequate prion-decontamination procedures like those recently implemented in dental practice must be rigorously enforced.

  7. Validation of 14-3-3 Protein as a Marker in Sporadic Creutzfeldt-Jakob Disease Diagnostic.

    PubMed

    Schmitz, Matthias; Ebert, Elisabeth; Stoeck, Katharina; Karch, André; Collins, Steven; Calero, Miguel; Sklaviadis, Theodor; Laplanche, Jean-Louis; Golanska, Ewa; Baldeiras, Ines; Satoh, Katsuya; Sanchez-Valle, Raquel; Ladogana, Anna; Skinningsrud, Anders; Hammarin, Anna-Lena; Mitrova, Eva; Llorens, Franc; Kim, Yong Sun; Green, Alison; Zerr, Inga

    2016-05-01

    At present, the testing of 14-3-3 protein in cerebrospinal fluid (CSF) is a standard biomarker test in suspected sporadic Creutzfeldt-Jakob disease (sCJD) diagnosis. Increasing 14-3-3 test referrals in CJD reference laboratories in the last years have led to an urgent need to improve established 14-3-3 test methods. The main result of our study was the validation of a commercially available 14-3-3 ELISA next to the commonly used Western blot method as a high-throughput screening test. Hereby, 14-3-3 protein expression was quantitatively analyzed in CSF of 231 sCJD and 2035 control patients. We obtained excellent sensitivity/specificity values of 88 and 96% that are comparable to the established Western blot method. Since standard protocols and preanalytical sample handling have become more important in routine diagnostic, we investigated in a further step the reproducibility and stability of 14-3-3 as a biomarker for human prion diseases. Ring trial data from 2009 to 2013 revealed an increase of Fleiss' kappa from 0.51 to 0.68 indicating an improving reliability of 14-3-3 protein detection. The stability of 14-3-3 protein under short-term and long-term storage conditions at various temperatures and after repeated freezing/thawing cycles was confirmed. Contamination of CSF samples with blood appears likely to be an important factor at a concentration of more than 2500 erythrocytes/μL. Hemolysis of erythrocytes with significant release of 14-3-3 protein started after 2 days at room temperature. We first define clear standards for the sample handling, short- and long-term storage of CSF samples as well as the handling of blood- contaminated samples which may result in artificially elevated CSF levels of 14-3-3.

  8. Visualization of viral candidate cDNAs in infectious brain fractions from Creutzfeldt-Jakob disease by representational difference analysis.

    PubMed

    Dron, M; Manuelidis, L

    1996-08-01

    Creutzfeldt-Jakob Disease (CJD), a neurodegenerative and dementing disease of later life, is caused by a viruslike entity that is incompletely characterized. As in scrapie, all more purified infectious brain preparations contain nucleic acids. However, it has not been possible to visualize unique bands that may derive from a viral genome. We here used a subtractive strategy known as representational difference analysis (RDA) to uncover such sequences. To reduce the complexity of starting target nucleic acids, sucrose gradients were first used to select nuclease resistant particles with a defined 120S size. In CJD this single 120S gradient peak is highly enriched for infectivity, and contains reduced amounts of PrP (Proc. Natl. Acad. Sci. 92, 5124-8, 1995). Parallel 120S fractions from uninfected brain were made to generate subtractor sequences. 120S particles were lysed in GdnSCN, and ng amounts of released RNA were purified for random-primed cDNA synthesis. To capture representative fragments of 100-500 bp, cDNAs were cleaved with Mbo I for adaptor ligation and amplification. In the first experiment with moderate RDA selection, it was possible to visualize clones from CJD cDNA that did not hybridize to control cDNA. In the second experiment, more exhaustive subtractions yielded a discrete set of CJD derived gel bands. Competitive hybridization showed a subset of these bands were not present in either the control 120S cDNA or in the hamster genome. This represents the first demonstration of apparently CJD-specific nucleic acid bands in more purified infectious preparations. Although exhaustive cloning, sequencing and correlative titration studies need to be done, it is encouraging that most of the viral candidates selected thus far have no significant homology with any previously described sequence in the database.

  9. CSF Concentrations of cAMP and cGMP Are Lower in Patients with Creutzfeldt-Jakob Disease but Not Parkinson's Disease and Amyotrophic Lateral Sclerosis

    PubMed Central

    Oeckl, Patrick; Steinacker, Petra; Lehnert, Stefan; Jesse, Sarah; Kretzschmar, Hans A.; Ludolph, Albert C.; Otto, Markus; Ferger, Boris

    2012-01-01

    Background The cyclic nucleotides cyclic adenosine-3′,5′-monophosphate (cAMP) and cyclic guanosine-3′,5′-monophosphate (cGMP) are important second messengers and are potential biomarkers for Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Creutzfeldt-Jakob disease (CJD). Methodology/Principal Findings Here, we investigated by liquid chromatography/tandem mass spectrometry (LC-MS/MS) the cerebrospinal fluid (CSF) concentrations of cAMP and cGMP of 82 patients and evaluated their diagnostic potency as biomarkers. For comparison with a well-accepted biomarker, we measured tau concentrations in CSF of CJD and control patients. CJD patients (n = 15) had lower cAMP (−70%) and cGMP (−55%) concentrations in CSF compared with controls (n = 11). There was no difference in PD, PD dementia (PDD) and ALS cases. Receiver operating characteristic (ROC) curve analyses confirmed cAMP and cGMP as valuable diagnostic markers for CJD indicated by the area under the curve (AUC) of 0.86 (cAMP) and 0.85 (cGMP). We calculated a sensitivity of 100% and specificity of 64% for cAMP and a sensitivity of 67% and specificity of 100% for cGMP. The combination of both nucleotides increased the sensitivity to 80% and specificity to 91% for the term cAMPxcGMP (AUC 0.92) and to 93% and 100% for the ratio tau/cAMP (AUC 0.99). Conclusions/Significance We conclude that the CSF determination of cAMP and cGMP may easily be included in the diagnosis of CJD and could be helpful in monitoring disease progression as well as in therapy control. PMID:22396786

  10. Population screening for variant Creutzfeldt-Jakob disease using a novel blood test: diagnostic accuracy and feasibility study.

    PubMed

    Jackson, Graham S; Burk-Rafel, Jesse; Edgeworth, Julie Ann; Sicilia, Anita; Abdilahi, Sabah; Korteweg, Justine; Mackey, Jonathan; Thomas, Claire; Wang, Guosu; Schott, Jonathan M; Mummery, Catherine; Chinnery, Patrick F; Mead, Simon; Collinge, John

    2014-04-01

    Our study indicates a prototype blood-based variant Creutzfeldt-Jakob disease (vCJD) assay has sufficient sensitivity and specificity to justify a large study comparing vCJD prevalence in the United Kingdom with a bovine spongiform encephalopathy-unexposed population. In a clinical diagnostic capacity, the assay's likelihood ratios dramatically change an individual's pretest disease odds to posttest probabilities and can confirm vCJD infection. To determine the diagnostic accuracy of a prototype blood test for vCJD and hence its suitability for clinical use and for screening prion-exposed populations. Retrospective, cross-sectional diagnostic study of blood samples from national blood collection and prion disease centers in the United States and United Kingdom. Anonymized samples were representative of the US blood donor population (n = 5000), healthy UK donors (n = 200), patients with nonprion neurodegenerative diseases (n = 352), patients in whom a prion disease diagnosis was likely (n = 105), and patients with confirmed vCJD (n = 10). Presence of vCJD infection determined by a prototype test (now in clinical diagnostic use) that captures, enriches, and detects disease-associated prion protein from whole blood using stainless steel powder. The assay's specificity among the presumed negative American donor samples was 100% (95% CI, 99.93%-100%) and was confirmed in a healthy UK cohort (100% specificity; 95% CI, 98.2%-100%). Of potentially cross-reactive blood samples from patients with nonprion neurodegenerative diseases, no samples tested positive (100% specificity; 95% CI, 98.9%-100%). Among National Prion Clinic referrals in whom a prion disease diagnosis was likely, 2 patients with sporadic CJD tested positive (98.1% specificity; 95% CI, 93.3%-99.8%). Finally, we reconfirmed but could not refine our previous sensitivity estimate in a small blind panel of samples from unaffected individuals and patients with vCJD (70% sensitivity; 95% CI, 34

  11. Sporadic—but Not Variant—Creutzfeldt-Jakob Disease Is Associated with Polymorphisms Upstream of PRNP Exon 1

    PubMed Central

    Mead, Simon; Mahal, Sukhvir P; Beck, John; Campbell, Tracy; Farrall, Martin; Fisher, Elizabeth; Collinge, John

    2001-01-01

    Human prion diseases have inherited, sporadic, and acquired etiologies. The appearance of the novel acquired prion disease, variant Creutzfeldt-Jakob disease (vCJD), and the demonstration that it is caused by the same prion strain as that causing bovine spongiform encephalopathy, has led to fears of a major human epidemic. The etiology of classical (sporadic) CJD, which has a worldwide incidence, remains obscure. A common human prion-protein–gene (PRNP) polymorphism (encoding either methionine or valine at codon 129) is a strong susceptibility factor for sporadic and acquired prion disease. However, a quantitative-trait–locus study of prion incubation periods in mice has demonstrated an important factor that is close to Prnp but is independent of its coding sequence or that of the nearby prion-like doppel gene (Prnd). We have analyzed the PRNP locus for such tightly linked susceptibility factors. Fifty-six polymorphic sites have been identified within 25 kb of the PRNP open reading frame, including sites within the PRNP promoter and the PRNP 3′ untranslated region. These have been characterized in 61 Centre d’Étude du Polymorphisme Humain (CEPH) families, demonstrating extensive linkage disequilibrium around PRNP and the existence of 11 major European PRNP haplotypes. Haplotype frequencies estimated in healthy U.K. control individuals were very similar to those deduced in the CEPH families. A common haplotype was overrepresented in patients with sporadic CJD (sCJD). Through use of a log-linear modeling approach to simultaneously model Hardy-Weinberg and linkage disequilibria, a significant independent association was found between sCJD and a polymorphism upstream of PRNP exon 1 (P=.005), in addition to the strong susceptibility conferred by codon 129 (P=2×10-8). However, although our sample size was necessarily small, no association was found between these polymorphisms and vCJD or iatrogenic CJD, in keeping with their having distinct disease mechanisms

  12. Biological network inferences for a protection mechanism against familial Creutzfeldt-Jakob disease with E200K pathogenic mutation

    PubMed Central

    2014-01-01

    Background Human prion diseases are caused by abnormal accumulation of misfolded prion protein in the brain tissue. Inherited prion diseases, including familial Creutzfeldt-Jakob disease (fCJD), are associated with mutations of the prion protein gene (PRNP). The glutamate (E)-to-lysine (K) substitution at codon 200 (E200K) in PRNP is the most common pathogenic mutation causing fCJD, but the E200K pathogenic mutation alone is regarded insufficient to cause prion diseases; thus, additional unidentified factors are proposed to explain the penetrance of E200K-dependent fCJD. Here, exome differences and biological network analysis between fCJD patients with E200K and healthy individuals, including a non-CJD individual with E200K, were analysed to gain new insights into possible mechanisms for CJD in individuals carrying E200K. Methods Exome sequencing of the three CJD patients with E200K and 11 of the family of one patient (case1) were performed using the Illumina HiSeq 2000. The exome sequences of 24 Healthy Koreans were used as control. The bioinformatic analysis of the exome sequences was performed using the CLC Genomics Workbench v5.5. Sanger sequencing for variants validation was processed using a BigDye Terminator Cycle Sequencing Kit and an ABI 3730xl automated sequencer. Biological networks were created using Cytoscape (v2.8.3 and v3.0.2) and Pathway Studio 9.0 software. Results Nineteen sites were only observed in healthy individuals. Four proteins (NRXN2, KLKB1, KARS, and LAMA3) that harbour rarely observed single-nucleotide variants showed biological interactions that are associated with prion diseases and/or prion protein in our biological network analysis. Conclusion Through this study, we confirmed that individuals can have a CJD-free life, even if they carry a pathogenic E200K mutation. Our research provides a possible mechanism that involves a candidate protective factor; this could be exploited to prevent fCJD onset in individuals carrying E200K. PMID

  13. Doxycycline in Creutzfeldt-Jakob disease: a phase 2, randomised, double-blind, placebo-controlled trial.

    PubMed

    Haïk, Stéphane; Marcon, Gabriella; Mallet, Alain; Tettamanti, Mauro; Welaratne, Arlette; Giaccone, Giorgio; Azimi, Shohreh; Pietrini, Vladimiro; Fabreguettes, Jean-Roch; Imperiale, Daniele; Cesaro, Pierre; Buffa, Carlo; Aucan, Christophe; Lucca, Ugo; Peckeu, Laurène; Suardi, Silvia; Tranchant, Christine; Zerr, Inga; Houillier, Caroline; Redaelli, Veronica; Vespignani, Hervé; Campanella, Angela; Sellal, François; Krasnianski, Anna; Seilhean, Danielle; Heinemann, Uta; Sedel, Frédéric; Canovi, Mara; Gobbi, Marco; Di Fede, Giuseppe; Laplanche, Jean-Louis; Pocchiari, Maurizio; Salmona, Mario; Forloni, Gianluigi; Brandel, Jean-Philippe; Tagliavini, Fabrizio

    2014-02-01

    Creutzfeldt-Jakob disease (CJD) is a fatal, untreatable prion encephalopathy. Previous studies showed that doxycycline is effective in in-vitro and in-vivo models of disease, and patients with CJD who received compassionate treatment with doxycycline showed increased survival time compared with historical series. We therefore did a randomised, double-blind study of doxycycline versus placebo in CJD. We recruited patients older than 18 years old who had a diagnosis of definite or probable sporadic CJD or genetic forms of the disease via Italian reference centres and the French national referral system. Patients were randomly assigned (ratio 1:1) to receive oral doxycycline (100 mg daily) or placebo under double-blind conditions from the day of randomisation to death. Centralised randomisation was done independently of enrolment or evaluation of patients using a minimisation method in Italy and a simple randomisation in France. Participants, caregivers, and clinicians were masked to group assignment. The primary efficacy variable was the survival time from randomisation. Interim analyses were planned to detect a significant effect of treatment as early as possible. This trial is registered with EudraCT, 2006-001858-27 for the Italian study and 2007-005553-34 for the French study. From April 12, 2007, to Aug 19, 2010, in Italy, and from Jan 30, 2009, to Jan 10, 2012, in France, 121 patients with CJD were enrolled in the study, 62 of whom were randomly assigned to the treatment group and 59 to the placebo group. The first interim analysis showed absence of superiority of doxycycline compared with placebo, and the trial was stopped for futility. Efficacy analyses did not show significant differences between patients treated with doxycycline and placebo with regard to survival times (HR 1.1, 95% CI 0.8-1.7, p=0.50). Serious adverse events were judged not to be related to treatment, whereas a relation was deemed probable or possible for five non-serious adverse events

  14. Nuclear DNA fragmentation in Creutzfeldt-Jakob disease: does a mere positive in situ nuclear end-labeling indicate apoptosis?

    PubMed

    Ferrer, I

    1999-01-01

    The method of in situ end-labeling of nuclear DNA fragmentation was used in the study of ten patients (two biopsies, eight autopsies) with sporadic Creutzfeldt-Jakob disease (CJD). All the patients had the typical morphological lesions including neuron loss, spongiform change and astrocytosis. Four of them also showed prion protein (PrP) deposits in the cerebral cortex, and two of them kuru-like plaques in the cerebellum. A few cells with DNA breaks were found in the two biopsy cases; one of them, suffering from a panencephalopathic form of the disease, showed positive nuclei not only in the cerebral cortex but also in the subcortical white matter. Variable numbers of positive nuclei were observed in the gray and white matter in the eight autopsy cases, in which, although the distribution of positive cells roughly correlated with the distribution of neuron loss, no clear relationship was found as regards the distribution and degree of cell labeling and the degree of neuron loss. Furthermore, large numbers of positive cells were concentrated in a particular area, whereas a few cells were seen in a neighboring equally affected area. Positive glial cells in the plexiform layer of the CA1 area of the hippocampus, and in the frontal white matter were frequently encountered. Staining of the cytoplasm in a minority of cells was interpreted as the result of nuclear DNA leakage. None of the stained cells had the typical morphology of apoptosis; most particularly, peripheral chromatin condensation and formation of apoptotic bodies were not seen in any case. PrP deposits did not result in an increase of nuclear DNA breaks either within the area or in adjacent regions. Although positive cells were also observed in autopsy cases of controls which were processed in the same way, positive labeling as a whole was higher in CJD than in age-matched controls. These results show that brain nuclear DNA is vulnerable in CJD, and suggest that increased DNA vulnerability has a role in

  15. Nosocomial transmission of sporadic Creutzfeldt-Jakob disease: results from a risk-based assessment of surgical interventions.

    PubMed

    de Pedro-Cuesta, Jesús; Mahillo-Fernández, Ignacio; Rábano, Alberto; Calero, Miguel; Cruz, Mabel; Siden, Ake; Laursen, Henning; Falkenhorst, Gerhard; Mølbak, Kåre

    2011-02-01

    Evidence of surgical transmission of sporadic Creutzfeldt-Jakob disease (sCJD) remains debatable in part due to misclassification of exposure levels. In a registry-based case-control study, the authors applied a risk-based classification of surgical interventions to determine the association between a history of surgery and sCJD. Case-control study, allowing for detailed analysis according to time since exposure. National populations of Denmark and Sweden. From national registries of Denmark and Sweden, the authors included 167 definite and probable sCJD cases with onset during the period 1987-2003, 835 age-, sex- and residence-matched controls and 2224 unmatched. Surgical procedures were categorised by anatomical structure and presumed risk of transmission level. The authors used logistic regression to determine the odds ratio (OR) for sCJD by surgical interventions in specified time-windows before disease-onset. From comparisons with matched controls, procedures involving retina and optic nerve were associated with an increased risk at a latency of ≥1 year OR (95% CI) 5.53 (1.08 to 28.0). At latencies of 10 to 19 years, interventions on peripheral nerves 4.41 (1.17 to 16.6) and skeletal muscle 1.58 (1.01 to 2.48) were directly associated. Interventions on blood vessels 4.54 (1.01 to 20.0), peritoneum 2.38 (1.14 to 4.96) and skeletal muscle 2.04 (1.06 to 3.92), interventions conducted by vaginal approach 2.26 (1.14 to 4.47) and a pooled category of lower-risk procedures 2.81 (1.62 to 4.88) had an increased risk after ≥20 years. Similar results were found when comparing with unmatched controls. This observation is in concordance with animal models of prion neuroinvasion and is likely to represent a causal relation of surgery with a non-negligible proportion of sCJD cases.

  16. Late-in-life surgery associated with Creutzfeldt-Jakob disease: a methodological outline for evidence-based guidance

    PubMed Central

    2013-01-01

    Background There is increasing epidemiological evidence of etiological links between general surgery and sporadic Creutzfeldt-Jakob disease (sCJD) with long incubation periods. The purpose of this study was to identify specific surgical procedures potentially associated with sCJD to be targeted for preventive presurgical-intervention guidance. Results We propose a three-step clinical guidance outline where surgical procedures associated with sCJD clinical onset – potentially more contaminant - are taken into account. Data on hospital discharges and surgical procedures were obtained from Danish and Swedish national in-patient hospital registries for 167 sCJD cases, onset 1987–2003, and for 835 matched and 2,224 unmatched population controls. Surgery was allocated to different life-time periods as previously reported, and frequencies were compared using logistic regression analysis. In the year preceding clinical onset, persons with sCJD underwent a statistically significant higher number of minor surgical interventions (OR (95% CI): 17.50 (3.64-84.24)), transluminal endoscopies (OR: 2.73 (1.01–7.37)) and gastrointestinal operations (OR: 3.51 (1.21–10.19)) compared to matched controls. Surgical discharges clustered towards clinical onset. These differences increased during the clinical period, with statistically significant higher frequencies for both endoscopies and minor surgery (OR: 13.91 (5.87-32.95), and for main surgical procedures (OR: 2.10 (1.00-4.39)), particularly gastrointestinal surgery (OR: 6.00 (1.83-19.66)), and surgery contacting skeletal muscle. Comparisons with unmatched controls yielded similar results for neurosurgery in the clinical period (OR: 19.40 (2.22-168.34)). Conclusions These results suggest that some types of surgical procedures are associated with sCJD, after clinical onset or particularly just before onset. Selective planning of such surgery to minimize instrument/device contamination or quarantining might be feasible

  17. Characterization of variant Creutzfeldt-Jakob disease prions in prion protein-humanized mice carrying distinct codon 129 genotypes.

    PubMed

    Takeuchi, Atsuko; Kobayashi, Atsushi; Ironside, James W; Mohri, Shirou; Kitamoto, Tetsuyuki

    2013-07-26

    To date, all clinical variant Creutzfeldt-Jakob disease (vCJD) patients are homozygous for methionine at polymorphic codon 129 (129M/M) of the prion protein (PrP) gene. However, the appearance of asymptomatic secondary vCJD infection in individuals with a PRNP codon 129 genotype other than M/M and transmission studies using animal models have raised the concern that all humans might be susceptible to vCJD prions, especially via secondary infection. To reevaluate this possibility and to analyze in detail the transmission properties of vCJD prions to transgenic animals carrying distinct codon 129 genotype, we performed intracerebral inoculation of vCJD prions to humanized knock-in mice carrying all possible codon 129 genotypes (129M/M, 129M/V, or 129V/V). All humanized knock-in mouse lines were susceptible to vCJD infection, although the attack rate gradually decreased from 129M/M to 129M/V and to 129V/V. The amount of PrP deposition including florid/amyloid plaques in the brain also gradually decreased from 129M/M to 129M/V and to 129V/V. The biochemical properties of protease-resistant abnormal PrP in the brain and transmissibility of these humanized mouse-passaged vCJD prions upon subpassage into knock-in mice expressing bovine PrP were not affected by the codon 129 genotype. These results indicate that individuals with the 129V/V genotype may be more susceptible to secondary vCJD infection than expected and may lack the neuropathological characteristics observed in vCJD patients with the 129M/M genotype. Besides the molecular typing of protease-resistant PrP in the brain, transmission studies using knock-in mice carrying bovine PrP may aid the differential diagnosis of secondary vCJD infection, especially in individuals with the 129V/V genotype.

  18. Creutzfeldt-Jakob-Like Syndrome due to Hypercalcemic Encephalopathy.

    PubMed

    Rösche, Johannes; Sieveking, Catharina; Kampf, Christina; Benecke, Reiner

    2015-10-01

    Hypercalcemia can cause a subacute syndrome of progressive dementia and marked changes in the electroencephalogram (EEG). We report a case of iatrogenic hypercalcemia with a close correlation between the clinical course and the EEG changes. A 73-year-old woman presented with a subacute syndrome of progressive dementia and bursts of 1.5 to 2 Hz intermittent rhythmic delta activity superimposed on a low-voltage background activity in the EEG. Clinical and EEG abnormalities rapidly resolved after normalization of serum calcium levels. As part of the diagnostic workup of a subacute progressive dementia, a serum calcium level and an EEG should be obtained to detect a Creutzfeldt-Jakob like syndrome in hypercalcemia. Unlike in Creutzfeldt-Jakob disease, and Creutzfeldt-Jakob-like syndrome induced by lithium intoxication, there are rarely myoclonic jerks and periodic discharges in hypercalcemic encephalopathy.

  19. Alternative application of Tau protein in Creutzfeldt-Jakob disease diagnosis: Improvement for weakly positive 14-3-3 protein in the laboratory.

    PubMed

    Hyeon, Jae Wook; Kim, Su Yeon; Lee, Jeongmin; Park, Jun Sun; Hwang, Kyu Jam; Lee, Sol Moe; An, SeongSoo A; Lee, Myung Koo; Ju, Young Ran

    2015-10-28

    The 14-3-3 protein has been used as a biomarker for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). However, weakly positive 14-3-3 leads to false positive results and an incorrect diagnosis. We attempted to use quantitative data for tau protein to provide an accurate diagnosis based on weak 14-3-3 protein. Sixty-two patients with sCJD, including pathologically confirmed, clinically definite, and probable cases, and 89 non-CJD patients were investigated based on a Korean population. Among them, 20 sCJD and 14 non-CJD showed weakly positive 14-3-3. The total tau (t-tau) and phosphorylated tau (p-tau) protein levels were measured by ELISA, and the p-tau to t-tau ratio (p/t ratio) was calculated. The combined use of the 14-3-3 protein assay, t-tau levels, and p/t ratio improved the specificity of diagnosis compared with the use of the 14-3-3 protein assay alone (47% for 14-3-3 alone; 85.94% for 14-3-3 combined with t-tau; 90.62% for 14-3-3 combined with the p/t ratio). In addition, 18 of 20 sCJD and 12 of 14 non-CJD who were weakly positive for 14-3-3 were positive for the p/t ratio and negative for the p/t ratio, respectively. When used in combination with the 14-3-3 protein, the tau protein is useful as a biomarker for the precise diagnosis of sCJD.

  20. Alternative application of Tau protein in Creutzfeldt-Jakob disease diagnosis: Improvement for weakly positive 14-3-3 protein in the laboratory

    PubMed Central

    Hyeon, Jae Wook; Kim, Su Yeon; Lee, Jeongmin; Park, Jun Sun; Hwang, Kyu Jam; Lee, Sol Moe; An, SeongSoo A.; Lee, Myung Koo; Ju, Young Ran

    2015-01-01

    The 14-3-3 protein has been used as a biomarker for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). However, weakly positive 14-3-3 leads to false positive results and an incorrect diagnosis. We attempted to use quantitative data for tau protein to provide an accurate diagnosis based on weak 14-3-3 protein. Sixty-two patients with sCJD, including pathologically confirmed, clinically definite, and probable cases, and 89 non-CJD patients were investigated based on a Korean population. Among them, 20 sCJD and 14 non-CJD showed weakly positive 14-3-3. The total tau (t-tau) and phosphorylated tau (p-tau) protein levels were measured by ELISA, and the p-tau to t-tau ratio (p/t ratio) was calculated. The combined use of the 14-3-3 protein assay, t-tau levels, and p/t ratio improved the specificity of diagnosis compared with the use of the 14-3-3 protein assay alone (47% for 14-3-3 alone; 85.94% for 14-3-3 combined with t-tau; 90.62% for 14-3-3 combined with the p/t ratio). In addition, 18 of 20 sCJD and 12 of 14 non-CJD who were weakly positive for 14-3-3 were positive for the p/t ratio and negative for the p/t ratio, respectively. When used in combination with the 14-3-3 protein, the tau protein is useful as a biomarker for the precise diagnosis of sCJD. PMID:26507666

  1. Multicentre multiobserver study of diffusion-weighted and fluid-attenuated inversion recovery MRI for the diagnosis of sporadic Creutzfeldt-Jakob disease: a reliability and agreement study.

    PubMed

    Fujita, Koji; Harada, Masafumi; Sasaki, Makoto; Yuasa, Tatsuhiko; Sakai, Kenji; Hamaguchi, Tsuyoshi; Sanjo, Nobuo; Shiga, Yusei; Satoh, Katsuya; Atarashi, Ryuichiro; Shirabe, Susumu; Nagata, Ken; Maeda, Tetsuya; Murayama, Shigeo; Izumi, Yuishin; Kaji, Ryuji; Yamada, Masahito; Mizusawa, Hidehiro

    2012-01-01

    Objectives To assess the utility of the display standardisation of diffusion-weighted MRI (DWI) and to compare the effectiveness of DWI and fluid-attenuated inversion recovery (FLAIR) MRI for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). Design A reliability and agreement study. Setting Thirteen MRI observers comprising eight neurologists and five radiologists at two universities in Japan. Participants Data of 1.5-Tesla DWI and FLAIR were obtained from 29 patients with sCJD and 13 controls. Outcome measures Standardisation of DWI display was performed utilising b0 imaging. The observers participated in standardised DWI, variable DWI (the display adjustment was observer dependent) and FLAIR sessions. The observers independently assessed each MRI for CJD-related lesions, that is, hyperintensity in the cerebral cortex or striatum, using a continuous rating scale. Performance was evaluated by the area under the receiver operating characteristics curve (AUC). Results The mean AUC values were 0.84 (95% CI 0.81 to 0.87) for standardised DWI, 0.85 (95% CI 0.82 to 0.88) for variable DWI and 0.68 (95% CI 0.63 to 0.72) for FLAIR, demonstrating the superiority of DWI (p<0.05). There was a trend for higher intraclass correlations of standardised DWI (0.74, 95% CI 0.66 to 0.83) and variable DWI (0.72, 95% CI 0.62 to 0.81) than that of FLAIR (0.63, 95% CI 0.53 to 0.74), although the differences were not statistically significant. Conclusions Standardised DWI is as reliable as variable DWI, and the two DWI displays are superior to FLAIR for the diagnosis of sCJD. The authors propose that hyperintensity in the cerebral cortex or striatum on 1.5-Tesla DWI but not FLAIR can be a reliable diagnostic marker for sCJD.

  2. Alien hand and leg as the presenting feature of probable sporadic Creutzfeldt-Jakob disease: A rare presentation of a rare disease

    PubMed Central

    Kumawat, Banshi Lal; Sharma, Chandra Mohan; Nath, Kunal; Acharya, Mihir; Khandelwal, Dinesh; Jain, Deepak

    2015-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) can have varied clinical presentation depending upon the genotype at codon 129. The common presenting clinical features of sCJD are rapid onset cognitive impairment, ataxia, psychosis and visual signs (field defects, distortion, cortical blindness). Alien limb sign was first described in patients with corpus callosal tumors and later with other neurodegenerative conditions like corticobasal degeneration. Alien hand complaints as the presenting feature of sCJD has been described in literature, but simultaneous alien hand and leg has been rarely described as presenting feature of sCJD. We describe here a case of a 55-year-old man who presented with progressive left alien hand and leg as the sole clinical manifestation of probable sCJD. PMID:25745324

  3. Creutzfeldt-Jakob Disease Fact Sheet for Healthcare Workers and Morticians

    MedlinePlus

    ... NINDS Focus on Research Bioengineering Epilepsy Health Disparities Neural Interfaces Parkinson's Disease Spinal Cord Injury Stem Cells ... NINDS Focus on Research Bioengineering Epilepsy Health Disparities Neural Interfaces Parkinson's Disease Spinal Cord Injury Stem Cells ...

  4. An experiential learning model applied to nurses working with patients with Creutzfeldt-Jakob disease.

    PubMed

    D'Amour, Rolande; Guimond, Pierrette

    2010-01-01

    Creutzfeldt-Jacob disease (C/D) is a rare neurological disease, transmissible, incurable and always fatal affecting humans, as well as animals. In the 1980s, the "mad cow disease" (MCD) epidemic in the United Kingdom popularized prion diseases worldwide. However, this contributed to the proliferation of disinformation, causing confusion between C/D and MCD in the public, as well as in some health care providers. The purpose of this article is to describe the process utilized to develop, implement, and evaluate a workshop on CJD for nurses and other health care providers. Kolb's experiential teaching/learning model was used as a framework for this workshop. A workbook was developed to complement the participants' learning. Fifteen health care providers from the Alzheimer Society of Canada's Dementia Network agreed to participate in this educational project. The results indicated that the participants had limited knowledge about C/D. They felt ill prepared and uncomfortable in providing quality care to this patient population. The workshop generated new insights and knowledge about the disease and the needs of the patients and their families. Participants exchanged ideas for tailored interventions. An experiential teaching/learning model is a highly effective approach to increase knowledge and skills, as well as fostering reflective practice.

  5. Possible underascertainment of variant Creutzfeldt-Jakob disease: a systematic study

    PubMed Central

    Hillier, C; Salmon, R; Neal, J; Hilton, D

    2002-01-01

    Objectives: To predict the size of the vCJD epidemic it is important to know whether the description of cases of vCJD in 1996 represent the first cases of a new disease entity or whether detection was due to increased surveillance of CJD in humans. Detection of earlier cases would suggest a shorter incubation period and might lead to predictions of epidemic size being revised. Methods: All certified deaths (excluding external injury and poisoning) in residents of Wales aged 15–45, between 1985 and 1995, were reviewed to detect vCJD deaths that might have been overlooked. 12 091 deaths were reviewed. "Non-specific fatal disorders compatible with vCJD" were defined. Deaths recorded to diseases other than those defined were rejected from further analysis (8769). Remaining cases (3322) were subdivided. Group A comprised deaths recorded to suicide, transport accidents, and those that could not be ascertained (ICD9 rubrics E950–959, E800–848, and 7999), a total of 2698 cases. Group B comprised deaths due to neurological disease, psychiatric disease, or substance abuse (624). Results: For group A, remaining brain material was identified (n=218, 8.1%) and examined by routine histology and immunocytochemistry for prion protein. No cases of vCJD were detected. For group B, review of remaining clinical information was undertaken. Of 624 cases, information was available on 447 (72%). Brain tissue was examined by routine histology and immunocytochemistry in 47 (7.5%) cases. Sufficient clinical and pathological information was available to exclude all these as potential cases of vCJD. Conclusion: Variant CJD is a new disease entity and not simply the result of better case ascertainment. PMID:11861685

  6. Unusual resistance to ionizing radiation of the viruses of kuru, Creutzfeldt-Jakob disease, and scrapie.

    PubMed

    Gibbs, C J; Gajdusek, D C; Latarjet, R

    1978-12-01

    The titers of several preparations of kuru. Creutzfeldt-Jacob disease, and scrapie viruses were reduced by only 1/10th or less by high doses of gamma radiation of 50 kGy and by only 1/10th-1/1000th or less for 200 kGy. This unusual radiation resistance of the two human viruses further links them with the scrapie virus and suggests that the genetic information of all three viruses is considerably smaller than that of any other known viruses of mammals.

  7. Unusual resistance to ionizing radiation of the viruses of kuru, Creutzfeldt-Jakob disease, and scrapie.

    PubMed Central

    Gibbs, C J; Gajdusek, D C; Latarjet, R

    1978-01-01

    The titers of several preparations of kuru. Creutzfeldt-Jacob disease, and scrapie viruses were reduced by only 1/10th or less by high doses of gamma radiation of 50 kGy and by only 1/10th-1/1000th or less for 200 kGy. This unusual radiation resistance of the two human viruses further links them with the scrapie virus and suggests that the genetic information of all three viruses is considerably smaller than that of any other known viruses of mammals. PMID:104301

  8. Sporadic Creutzfeldt-Jakob Disease Causing a 2-Years Slowly Progressive Isolated Dementia

    PubMed Central

    Machado, Álvaro; Ribeiro, Manuel; Rodrigues, Margarida; Ferreira, Carla; Baldeiras, Inês; Ribeiro, M. Helena; Santana, Isabel; Almeida, Rui; Castro, Lígia; Carpenter, Stirling

    2009-01-01

    A 47-year-old woman was seen for progressive behavioural and cognitive disturbances slowly evolving over a 1-year period. Neuropsychological evaluation disclosed moderate to severe impairment of all cortical functions. Besides this no other clinical abnormality was found. MRI diffusion weighted imaging disclosed hyperintense cortical lesions in a ribbon-like fashion, with restricted diffusivity. EEG showed no periodic sharp waves and CSF examination was normal, including protein 14.3.3. She was heterozygote on codon 129. Her cognitive function continued to decline and she was readmitted for further investigation at the 24th month of disease. Again no ataxia or involuntary movements were observed. MRI disclosed widespread hyperintense lesions over the entire cortex and, for the first time, also caudato-putaminal hyperintensity in T2-weighted images. EEG again failed to show periodic activity. Stereotactic biopsy disclosed moderate spongiform changes, astrocytosis and perivacuolar staining with prion-directed antibodies. Western blot analysis revealed prion type 2 mobility pattern. We discuss the clinical significance of this case: as dementia was the sole finding, and this was slowly-evolving over a 2-year period, MRI findings were the key factor suggesting a prion disease in a woman that otherwise would probably be diagnosed with a primary degenerative dementia. PMID:19996514

  9. Creutzfeldt-Jakob Disease with a prion protein gene codon 180 mutation presenting asymmetric cortical high-intensity on magnetic resonance imaging.

    PubMed

    Amano, Yuko; Kimura, Noriyuki; Hanaoka, Takuya; Aso, Yasuhiro; Hirano, Teruyuki; Murai, Hiroyuki; Satoh, Katsuya; Matsubara, Etsuro

    2015-01-01

    Here we report a genetically confirmed case of Creutzfeldt-Jakob disease with a prion protein gene codon 180 mutation presenting atypical magnetic resonance imaging findings. The present case exhibited an acute onset and lateralized neurologic signs, and progressive cognitive impairment. No myoclonus or periodic synchronous discharges on electroencephalography were observed. Diffusion-weighted images revealed areas of high signal intensity in the right frontal and temporal cortices at onset that extended to the whole cortex and basal ganglia of the right cerebral hemisphere at 3 months. Although the cerebrospinal fluid (CSF) was initially negative for neuron specific enolase, tau protein, 14-3-3 protein, and abnormal prion protein, the CSF was positive for these brain-derived proteins at 3 months after onset.

  10. Sporadic MM2-thalamic + cortical Creutzfeldt-Jakob disease: Utility of diffusion tensor imaging in the detection of cortical involvement in vivo.

    PubMed

    Grau-Rivera, Oriol; Sánchez-Valle, Raquel; Bargalló, Nuria; Lladó, Albert; Gaig, Carles; Nos, Carlos; Ferrer, Isidre; Graus, Francesc; Gelpi, Ellen

    2016-04-01

    In sporadic Creutzfeldt-Jakob disease (sCJD), high signal intensity in fluid attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) sequences in striatum and/or cortical regions of the brain are present in about 83% of cases, reflecting tissue damage, such as spongiform change and abnormal prion protein deposits. Novel diffusion sequences of MRI might improve the detection of CJD characteristic changes in the subset of patients in whom these alterations are absent or less evident. We report a neuropathologically confirmed case of the rare MM2 T + C subtype of sCJD, with mixed clinical and neuropathological features of MM2 thalamic and MM2 cortical subtypes, in whom the use of diffusion tensor imaging helped to identify cortical hyperintensities that could be easily overlooked with conventional DWI.

  11. Proteomic analysis of host brain components that bind to infectious particles in Creutzfeldt-Jakob disease

    PubMed Central

    Kipkorir, Terry; Colangelo, Christopher M.; Manuelidis, Laura

    2015-01-01

    Transmissible encephalopathies (TSEs), such as CJD and scrapie, are caused by infectious agents that provoke strain-specific patterns of disease. Misfolded host prion protein (PrP-res amyloid) is believed to be the causal infectious agent. However, particles that are stripped of PrP retain both high infectivity and viral proteins not detectable in uninfected mouse controls. We here detail host proteins bound with FU-CJD infectious brain particles by proteomic analysis. More than 98 proteins were differentially regulated, and 56 FU-CJD exclusive proteins were revealed after PrP, GFAP, C1q, ApoE and other late pathologic response proteins were removed. Stripped FU-CJD particles revealed HSC70 (144× the uninfected control), cyclophilin B, an FU-CJD exclusive protein required by many viruses, and early endosome-membrane pathways known to facilitate viral processing, replication, and spread. Synaptosomal elements including synapsin-2 (at 33×) and AP180 (a major FU-CJD exclusive protein) paralleled the known ultrastructural location of 25nm virus-like TSE particles and infectivity in synapses. Proteins without apparent viral or neurodegenerative links (copine-3), and others involved in viral-induced protein misfolding and aggregation, were also identified. Human sCJD brain particles contained 146 exclusive proteins, and heat shock, synaptic and viral pathways were again prominent, in addition to Alzheimer (AD), Parkinson, and Huntington aggregation proteins. Host proteins that bind TSE infectious particles can prevent host immune recognition and contribute to prolonged cross-species transmissions (the species barrier). Our infectious particle strategy, which reduces background sequences by >99%, emphasizes host targets for new therapeutic initiatives. Such therapies can simultaneously subvert common pathways of neurodegeneration. PMID:25930988

  12. Imaging astrocytosis with PET in Creutzfeldt-Jakob disease: case report with histopathological findings

    PubMed Central

    Engler, Henry; Nennesmo, Inger; Kumlien, Eva; Gambini, Juan Pablo; Lundberg, PO; Savitcheva, Irina; Långström, Bengt

    2012-01-01

    In a previous study, patients with suspect Creutzfeldt-Jakob’s disease (CJD) have been examined with Positron Emission Tomography (PET) combining N-[11C-methyl]-L-deuterodeprenyl (DED) and [18F] 2- fluorodeoxyglucose (FDG) in an attempt to detect astrocytosis and neuronal dysfunction, two of the hallmarks in CJD. Increased DED uptake with pronounced hypometabolism matching the areas with high DED retention was found in the fronto-parieto-occipital areas and cerebellum of patients with confirmed CJD. However, the temporal lobes did not present such a pattern. In 6 of the 15 examined patients the autopsy was performed, but a strict comparison between the PET results and the histopathology could not be done. Recently, one patient with suspect CJD was examined with PET using DED and FDG. The results of the examinations in this patient showed a pattern similar to that found in the brain of the CJD patients from the first study. The patient died shortly after the examination and an autopsy could be performed. The autopsy showed neuronal death, astrocytosis and spongiform changes in the brain. The diagnosis of definite sporadic CJD was established by the Western blot analysis, confirming the presence of the prion resistant protein (PrPres). The PET data demonstrated high DED uptake and extreme low glucose uptake in the left brain hemisphere whereas the right side was less affected. The autopsy was performed allowing the comparison between high DED uptake and the histopathological findings of reactive astrocytosis revealed by immunostaining with antibodies against glial fibrillary acid protein (GFAP). The results confirmed the presence of a pattern with high ratio DED/FDG, similar to that found in the previous study and revealing for the first time, a good correlation between high DED uptake and high density of reactive astrocytes as demonstrated by immunostaining. PMID:22567182

  13. Creutzfeldt-Jakob Disease

    MedlinePlus

    ... that surrounds the brain and spinal cord, and magnetic resonance imaging.. The first concern is to rule out treatable ... that surrounds the brain and spinal cord, and magnetic resonance imaging.. The first concern is to rule out treatable ...

  14. Creutzfeldt-Jakob Disease

    MedlinePlus

    ... CJD, v-CJD), described in Great Britain and France-begins primarily with psychiatric symptoms, affects younger individuals ... younger than average people in Great Britain and France has led to concern that BSE may be ...

  15. Creutzfeldt-Jakob disease with the M232R mutation in the prion protein gene in two cases showing different disease courses: a clinicopathological study.

    PubMed

    Takeda, Naoya; Yokota, Osamu; Terada, Seishi; Haraguchi, Takashi; Nobukuni, Keigo; Mizuki, Reiko; Honda, Hajime; Yoshida, Hidenori; Kishimoto, Yuki; Oshima, Etsuko; Ishizu, Hideki; Satoh, Katsuya; Kitamoto, Tetsuyuki; Ihara, Yuetsu; Uchitomi, Yosuke

    2012-01-15

    We report two autopsy cases of Creutzfeldt-Jakob disease (CJD) with the M232R mutation of the prion protein (PrP) gene that exhibited different clinicopathological features (age at death, 64/54 years; disease duration, 13/26 months). Both cases showed myoclonus, hyperintensity on diffusion-weighted MRI, and increased 14-3-3 protein in the cerebrospinal fluid. The initial sign in each case was memory disturbance and abnormal pharyngeal sensation, respectively. In the first case, the disease progressed rapidly with akinetic mutism developing 6 months after onset, while it occurred 23 months after onset in the second case. Pathologically, both cases had severe neuronal loss with gliosis and spongiform change in the cerebral cortex, basal ganglia, and cerebellum. PrP deposition was the diffuse synaptic type in the first case, but the second case had both diffuse synaptic and perivacuolar types. PrP(sc) immunoblotting revealed a type 1 band pattern in the first case, but both types 1 and 2 in the second case. Based on these findings, together with the results in previous CJD cases with M232R, we noted the possibility that the presence of type 2 PrP(sc) may be associated with both morphological features of PrP deposition and slow disease progression in this genetic prion disease. Copyright © 2011 Elsevier B.V. All rights reserved.

  16. Relation between clinical findings and progression of cerebral cortical pathology in MM1-type sporadic Creutzfeldt-Jakob disease: proposed staging of cerebral cortical pathology.

    PubMed

    Iwasaki, Yasushi; Tatsumi, Shinsui; Mimuro, Maya; Kitamoto, Tetsuyuki; Hashizume, Yoshio; Yoshida, Mari

    2014-06-15

    In our pathologic observation of the cerebral cortex including the neocortex, hippocampus, and limbic cortex in 43 Japanese patients with MM1-type sporadic Creutzfeldt-Jakob disease, the earliest pathologic finding was spongiform change and next was gliosis. Subsequently, neuropil rarefaction appeared, followed by neuron loss. On the basis of these observations, we propose the following cortical pathologic staging: Stage I, spongiform change; Stage II, hypertrophic astrocytosis; Stage III, neuropil rarefaction; Stage IV, neuron loss; Stage V, status spongiosus; and Stage VI, large cavity formation. We also suggest a more simple staging classification: Stages I and II, mild; Stages III and IV, moderate; and Stages V and VI, severe involvement. Based on statistical analysis of the cases, strong correlation coefficients were obtained between the neocortical and limbic pathologic stage and both total disease duration and brain weight. We estimated that the first observation times of cortical hyperintensity on diffusion-weighted images of magnetic resonance imaging, myoclonus, and periodic sharp wave complexes on the electroencephalogram approximately correspond to the early phase of Stage II of the neocortex. The time to reach the akinetic mutism state approximately corresponds to the middle phase of Stage II of the neocortex. Therefore, we think that approximate clinical manifestations at death, total disease duration, and brain weight can be estimated according to the pathologic stage of the neocortex or limbic cortex. Panencephalopathic-type pathology appeared approximately 12 months after disease onset, and this time approximately corresponds to the middle phase of Stage III of the neocortex.

  17. Systematic reviews in paediatric multiple sclerosis and Creutzfeldt-Jakob disease exemplify shortcomings in methods used to evaluate therapies in rare conditions.

    PubMed

    Unkel, Steffen; Röver, Christian; Stallard, Nigel; Benda, Norbert; Posch, Martin; Zohar, Sarah; Friede, Tim

    2016-02-20

    Randomized controlled trials (RCTs) are the gold standard design of clinical research to assess interventions. However, RCTs cannot always be applied for practical or ethical reasons. To investigate the current practices in rare diseases, we review evaluations of therapeutic interventions in paediatric multiple sclerosis (MS) and Creutzfeldt-Jakob disease (CJD). In particular, we shed light on the endpoints used, the study designs implemented and the statistical methodologies applied. We conducted literature searches to identify relevant primary studies. Data on study design, objectives, endpoints, patient characteristics, randomization and masking, type of intervention, control, withdrawals and statistical methodology were extracted from the selected studies. The risk of bias and the quality of the studies were assessed. Twelve (seven) primary studies on paediatric MS (CJD) were included in the qualitative synthesis. No double-blind, randomized placebo-controlled trial for evaluating interventions in paediatric MS has been published yet. Evidence from one open-label RCT is available. The observational studies are before-after studies or controlled studies. Three of the seven selected studies on CJD are RCTs, of which two received the maximum mark on the Oxford Quality Scale. Four trials are controlled observational studies. Evidence from double-blind RCTs on the efficacy of treatments appears to be variable between rare diseases. With regard to paediatric conditions it remains to be seen what impact regulators will have through e.g., paediatric investigation plans. Overall, there is space for improvement by using innovative trial designs and data analysis techniques.

  18. UK Iatrogenic Creutzfeldt-Jakob disease: investigating human prion transmission across genotypic barriers using human tissue-based and molecular approaches.

    PubMed

    Ritchie, Diane L; Barria, Marcelo A; Peden, Alexander H; Yull, Helen M; Kirkpatrick, James; Adlard, Peter; Ironside, James W; Head, Mark W

    2017-04-01

    Creutzfeldt-Jakob disease (CJD) is the prototypic human prion disease that occurs most commonly in sporadic and genetic forms, but it is also transmissible and can be acquired through medical procedures, resulting in iatrogenic CJD (iCJD). The largest numbers of iCJD cases that have occurred worldwide have resulted from contaminated cadaveric pituitary-derived human growth hormone (hGH) and its use to treat primary and secondary growth hormone deficiency. We report a comprehensive, tissue-based and molecular genetic analysis of the largest series of UK hGH-iCJD cases reported to date, including in vitro kinetic molecular modelling of genotypic factors influencing prion transmission. The results show the interplay of prion strain and host genotype in governing the molecular, pathological and temporal characteristics of the UK hGH-iCJD epidemic and provide insights into the adaptive mechanisms involved when prions cross genotypic barriers. We conclude that all of the available evidence is consistent with the hypothesis that the UK hGH-iCJD epidemic resulted from transmission of the V2 human prion strain, which is associated with the second most common form of sporadic CJD.

  19. An autopsy case of Creutzfeldt-Jakob disease with a V180I mutation of the PrP gene and Alzheimer-type pathology.

    PubMed

    Yoshida, Hidenori; Terada, Seishi; Ishizu, Hideki; Ikeda, Kenji; Hayabara, Toshiyuki; Ikeda, Kazuyo; Deguchi, Kazushi; Touge, Tetsuo; Kitamoto, Tetsuyuki; Kuroda, Shigetoshi

    2010-04-01

    We report an autopsy case of Creutzfeldt-Jakob disease with a codon 180 point mutation of the prion protein gene (PRNP). A 77-year-old woman developed gait instability, followed by dementia and limb/truncal ataxia. She became akinetic and mute 18 months and died of pneumonia 26 months after the disease onset. Analysis of the PRNP gene revealed a codon 180 point mutation. Post-mortem examination revealed marked spongiosis, neuronal loss, and astrocytic gliosis in the cerebral cortex. Mild to moderate spongiosis and neuronal loss were observed in the limbic cortex and basal ganglia. There was no spongiform change in the hippocampus, brain stem or cerebellum. Many senile plaques and neurofibrillary tangles were found, and the Braak stages were stage C and stage IV, respectively. Immunostaining for prion protein (PrP) revealed granular (synaptic-type) and patchy PrP deposition in the cerebral cortex and especially in the hippocampus. Most patchy PrP deposits were colocalized with amyloid beta plaques, but some of them were isolated. The relatively strong PrP deposition and coexistence of Alzheimer-type pathology of this case are remarkable. We suppose that amyloid beta plaques might act as a facilitating factor for PrP deposition.

  20. An autopsy case of Creutzfeldt-Jakob disease with a prion protein gene codon 180 mutation presenting with pathological laughing and an exaggerated startle reaction.

    PubMed

    Iwasaki, Yasushi; Mori, Keiko; Ito, Masumi; Akagi, Akio; Mimuro, Maya; Kitamoto, Tetsuyuki; Yoshida, Mari

    2017-07-13

    A 78-year-old Japanese woman presented with slow progressive disorientation and memory disturbances. Pathological laughing was observed at an early disease stage and continued for several months. Around the same time, the patient began to exhibit an exaggerated startle reaction and mild myoclonus. The pathological laughing and startle reaction disappeared before the patient reached an akinetic mutism state approximately 16 months after symptom onset. MRI showed extensive hyperintensity of the cerebral cortex and striatum on diffusion-weighted images, and swelling in the cerebral cortex on T2-weighted and fluid attenuated inversion recovery images. A prion protein (PrP) gene analysis revealed a V180I mutation with methionine homozygosity at codon 129. Neuropathological examination showed extensive spongiform changes with characteristic various-sized and non-confluent (VaSNoC) vacuoles in the cerebral neocortex and striatum. Gliosis and hypertrophic astrocytosis were generally mild in character. Neurons were relatively preserved in number. We believe that pathological laughing and an exaggerated startle reaction are possible pathognomonic findings of V180I genetic Creutzfeldt-Jakob disease. Based on the pathological findings of the present case, the presence of the VaSNoC-type spongiform changes with relative preservation of the neurons in the cerebral cortex and a lack of apparent brainstem involvement are associated at least in part with the pathological laughing and startle reaction. © 2017 Japanese Society of Neuropathology.

  1. Sensitivity to biases of case-control studies on medical procedures, particularly surgery and blood transfusion, and risk of Creutzfeldt-Jakob disease.

    PubMed

    de Pedro Cuesta, Jesús; Ruiz Tovar, María; Ward, Hester; Calero, Miguel; Smith, Andrew; Verduras, Concepción Alonso; Pocchiari, Maurizio; Turner, Marc L; Forland, Frode; Palm, Daniel; Will, Robert G

    2012-01-01

    Evidence of risk of Creutzfeldt-Jakob disease (CJD) associated with medical procedures, including surgery and blood transfusion, is limited by susceptibility to bias in epidemiological studies. Sensitivity to bias was explored using a central-birth-cohort model using data from 18 case-control studies obtained after a review of 494 reports on medical procedures and risk of CJD, systematic for the period January 1, 1989 to December 31, 2011. The validity of the findings in these studies may have been undermined by: recall; control selection; exposure assessment in life-time periods of different duration, out of time-at-risk of effect, or asymmetry in case/control data; and confounding by concomitant blood transfusion at the time of surgery. For sporadic CJD (sCJD), a history of surgery or blood transfusion was associated with risk in some, but not all, recent studies at a ≥10 year lag time, when controls were longitudinally sampled. Space-time aggregation of surgical events was not seen. Surgery at early clinical onset might be overrepresented among cases. Neither surgical history nor blood transfusion unlabelled for donor status, dental treatments or endoscopic examinations were linked to variant CJD (vCJD). These results indicate the need for further research. Common challenges within these studies include access to and content of past medical/dental treatment records for diseases with long incubation periods. Copyright © 2012 S. Karger AG, Basel.

  2. Insights into the management of emerging infections: regulating variant Creutzfeldt-Jakob disease transfusion risk in the UK and the US.

    PubMed

    Ponte, Maya L

    2006-10-01

    Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease caused by infection with the agent of bovine spongiform encephalopathy. After the recognition of vCJD in the UK in 1996, many nations implemented policies intended to reduce the hypothetical risk of transfusion transmission of vCJD. This was despite the fact that no cases of transfusion transmission had yet been identified. In December 2003, however, the first case of vCJD in a recipient of blood from a vCJD-infected donor was announced. The aim of this study is to ascertain and compare the factors that influenced the motivation for and the design of regulations to prevent transfusion transmission of vCJD in the UK and US prior to the recognition of this case. A document search was conducted to identify US and UK governmental policy statements and guidance, transcripts (or minutes when transcripts were not available) of scientific advisory committee meetings, research articles, and editorials published in medical and scientific journals on the topic of vCJD and blood transfusion transmission between March 1996 and December 2003. In addition, 40 interviews were conducted with individuals familiar with the decision-making process and/or the science involved. All documents and transcripts were coded and analyzed according to the methods and principles of grounded theory. Data showed that while resulting policies were based on the available science, social and historical factors played a major role in the motivation for and the design of regulations to protect against transfusion transmission of vCJD. First, recent experience with and collective guilt resulting from the transfusion-transmitted epidemics of HIV/AIDS in both countries served as a major, historically specific impetus for such policies. This history was brought to bear both by hemophilia activists and those charged with regulating blood products in the US and UK. Second, local specificities, such as the recall of blood products for possible

  3. Insights into the Management of Emerging Infections: Regulating Variant Creutzfeldt-Jakob Disease Transfusion Risk in the UK and the US

    PubMed Central

    Ponte, Maya L

    2006-01-01

    Background Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease caused by infection with the agent of bovine spongiform encephalopathy. After the recognition of vCJD in the UK in 1996, many nations implemented policies intended to reduce the hypothetical risk of transfusion transmission of vCJD. This was despite the fact that no cases of transfusion transmission had yet been identified. In December 2003, however, the first case of vCJD in a recipient of blood from a vCJD-infected donor was announced. The aim of this study is to ascertain and compare the factors that influenced the motivation for and the design of regulations to prevent transfusion transmission of vCJD in the UK and US prior to the recognition of this case. Methods and Findings A document search was conducted to identify US and UK governmental policy statements and guidance, transcripts (or minutes when transcripts were not available) of scientific advisory committee meetings, research articles, and editorials published in medical and scientific journals on the topic of vCJD and blood transfusion transmission between March 1996 and December 2003. In addition, 40 interviews were conducted with individuals familiar with the decision-making process and/or the science involved. All documents and transcripts were coded and analyzed according to the methods and principles of grounded theory. Data showed that while resulting policies were based on the available science, social and historical factors played a major role in the motivation for and the design of regulations to protect against transfusion transmission of vCJD. First, recent experience with and collective guilt resulting from the transfusion-transmitted epidemics of HIV/AIDS in both countries served as a major, historically specific impetus for such policies. This history was brought to bear both by hemophilia activists and those charged with regulating blood products in the US and UK. Second, local specificities, such as the recall

  4. Correlation between periodic sharp wave complexes and diffusion-weighted magnetic resonance images in early stage of Creutzfeldt-Jakob disease: a report of two cases.

    PubMed

    Mizobuchi, Masahiro; Tanaka, Chiharu; Sako, Kazuya; Nihira, Atsuko; Abe, Takenori; Shirasawa, Atsushi

    2008-12-01

    We evaluated the correlation between the periodic sharp wave complexes (PSWC) on EEG and the spreading lesions on diffusion-weighted (DW) magnetic resonance images (MRI) in two cases of Creutzfeldt-Jakob disease (CJD). In Case 1, DW-MRI showed increased signal intensity in bilateral caudate, bilateral parietal, and right temporo-occipital cortex at 7 weeks after onset. EEG showed PSWC of 1Hz frequency at 8 weeks after onset. Source localization analysis of the PSWC was conducted by low resolution electromagnetic tomography (LORETA), and localized the source in the cortex of bilateral parietal lobes and mesial frontal lobe, predominantly on the right side. At 10 weeks after onset, the PSWC source spread to bilateral parietal and frontal lobes, and the same spread was also observed for the lesion depicted on DW-MRI. In Case 2, DW images showed high signal intensity in the right parietal cortical lesion at 4 weeks after onset. PSWC of 2Hz frequency were seen in the routine EEG, and the source was localized in bilateral frontal lobes and right parietal lobe at 7 weeks after onset. The lesions on DW images also spread to bilateral frontal and parietal lobes. Nine weeks after onset, the source of PSWC extended to the right frontal lobe and bilateral parietal lobes, while the lesions on DW images progressed to the right temporal lobe and bilateral fronto-parieto-occipital lobes. Spreading DW-MRI lesions may correlate with the appearance of PSWC.

  5. 14-3-3 Protein isoforms and atypical patterns of the 14-3-3 assay in the diagnosis of Creutzfeldt-Jakob disease.

    PubMed

    Sánchez-Valle, Raquel; Saiz, Albert; Graus, Francesc

    2002-03-01

    A positive 14-3-3 assay is a criterion for probable Creutzfeldt-Jakob disease (CJD). Cerebrospinal fluid (CSF) 14-3-3 is usually detected by immunoblot using an antibody that recognizes all of the 14-3-3 isoforms. In a few cases, the antibody recognizes an inferior band and this pattern is associated with false positive results. We analyzed 43 CSF (26 CJD, 17 controls) samples using antibodies against specific isoforms (beta, epsilon, gamma, tau, xi) and compared the results with those obtained with the standard antibody. The anti-gamma and anti-beta antibody achieved similar results but the presence of atypical patterns made the standard antibody more accurate for the CJD diagnosis. To study the nature of the inferior band, CSF samples were probed with antibodies against light chain immunoglobulins, and immunoblots of human IgG with the standard antibody. The experiments suggested a cross-reaction of the anti-14-3-3 antibody with light chain immunoglobulins.

  6. PrP mRNA and protein expression in brain and PrPc in CSF in Creutzfeldt-Jakob disease MM1 and VV2

    PubMed Central

    Llorens, Franc; Ansoleaga, Belén; Garcia-Esparcia, Paula; Zafar, Saima; Grau-Rivera, Oriol; López-González, Irene; Blanco, Rosi; Carmona, Margarita; Yagüe, Jordi; Nos, Carlos; del Río, José Antonio; Gelpí, Ellen; Zerr, Inga; Ferrer, Isidre

    2013-01-01

    Creutzfeldt-Jakob disease (CJD) is a heterogenic neurodegenerative disorder associated with abnormal post-translational processing of cellular prion protein (PrPc). CJD displays distinctive clinical and pathological features which correlate with the genotype at the codon 129 (methionine or valine: M or V respectively) in the prion protein gene and with size of the protease-resistant core of the abnormal prion protein PrPsc (type 1: 20/21 kDa and type 2: 19 kDa). MM1 and VV2 are the most common sporadic CJD (sCJD) subtypes. PrP mRNA expression levels in the frontal cortex and cerebellum are reduced in sCJD in a form subtype-dependent. Total PrP protein levels and PrPsc levels in the frontal cortex and cerebellum accumulate differentially in sCJD MM1 and sCJD VV2 with no relation between PrPsc deposition and spongiform degeneration and neuron loss, but with microgliosis, and IL6 and TNF-α response. In the CSF, reduced PrPc, the only form present in this compartment, occurs in sCJD MM1 and VV2. PrP mRNA expression is also reduced in the frontal cortex in advanced stages of Alzheimer disease, Lewy body disease, progressive supranuclear palsy, and frontotemporal lobe degeneration, but PrPc levels in brain varies from one disease to another. Reduced PrPc levels in CSF correlate with PrP mRNA expression in brain, which in turn reflects severity of degeneration in sCJD. PMID:24047819

  7. PrP mRNA and protein expression in brain and PrP(c) in CSF in Creutzfeldt-Jakob disease MM1 and VV2.

    PubMed

    Llorens, Franc; Ansoleaga, Belén; Garcia-Esparcia, Paula; Zafar, Saima; Grau-Rivera, Oriol; López-González, Irene; Blanco, Rosi; Carmona, Margarita; Yagüe, Jordi; Nos, Carlos; Del Río, José Antonio; Gelpí, Ellen; Zerr, Inga; Ferrer, Isidre

    2013-01-01

    Creutzfeldt-Jakob disease (CJD) is a heterogenic neurodegenerative disorder associated with abnormal post-translational processing of cellular prion protein (PrP(c)). CJD displays distinctive clinical and pathological features which correlate with the genotype at the codon 129 (methionine or valine: M or V respectively) in the prion protein gene and with size of the protease-resistant core of the abnormal prion protein PrP(sc) (type 1: 20/21 kDa and type 2: 19 kDa). MM1 and VV2 are the most common sporadic CJD (sCJD) subtypes. PrP mRNA expression levels in the frontal cortex and cerebellum are reduced in sCJD in a form subtype-dependent. Total PrP protein levels and PrP(sc) levels in the frontal cortex and cerebellum accumulate differentially in sCJD MM1 and sCJD VV2 with no relation between PrP(sc) deposition and spongiform degeneration and neuron loss, but with microgliosis, and IL6 and TNF-α response. In the CSF, reduced PrP(c), the only form present in this compartment, occurs in sCJD MM1 and VV2. PrP mRNA expression is also reduced in the frontal cortex in advanced stages of Alzheimer disease, Lewy body disease, progressive supranuclear palsy, and frontotemporal lobe degeneration, but PrP(c) levels in brain varies from one disease to another. Reduced PrP(c) levels in CSF correlate with PrP mRNA expression in brain, which in turn reflects severity of degeneration in sCJD.

  8. An autopsied case of MV2K + C-type sporadic Creutzfeldt-Jakob disease presenting with widespread cerebral cortical involvement and Kuru plaques.

    PubMed

    Iwasaki, Yasushi; Saito, Yufuko; Aiba, Ikuko; Kobayashi, Atsushi; Mimuro, Maya; Kitamoto, Tetsuyuki; Yoshida, Mari

    2017-06-01

    MV2-type sporadic Creutzfeldt-Jakob disease (sCJD), which was previously called "Kuru-plaque variant", was gradually revealed to have a wide spectrum and has been classified into three pathological subtypes: MV2K, MV2C and MV2K + C. We herein describe the detailed clinical findings and neuropathologic observations from an autopsied MV2K + C-type Japanese sCJD case with widespread cerebral cortical pathology and Kuru plaques. In the early stages of the disease, the patient exhibited gait disturbance with ataxia and dysarthria as well as gradual appearance of cognitive dysfunction. Diffusion-weighted images (DWI) on MRI revealed extensive cerebral cortical hyperintensity. Pathologic investigation revealed extensive spongiform change in the cerebral cortex, particularly in the deeper layers. Vacuole size varied, and some were confluent. Prion protein (PrP) immunostaining revealed extensive PrP deposition in the cerebral cortex, basal ganglia, thalamus, cerebellum, brainstem and spinal cord. In the cerebral cortex, synaptic-type, Kuru plaque-like, and coarse plaque-type PrP depositions were mainly observed, along with some perivacuolar-type PrP depositions. Kuru plaques and coarse plaque-type PrP depositions also were observed in the cerebellar cortex. PrP gene analysis revealed no mutations, and polymorphic codon 129 exhibited Met/Val heterozygosity. Western blot analysis revealed a mixture of intermediate-type PrP(Sc) and type 2 PrP(Sc) . Based on previous reports regarding MV2-type sCJD and the clinicopathologic findings of the present case, we speculated that it may be possible to clinically distinguish each MV2 subtype. Clinical presentation of the MV2K + C subtype includes predominant cerebral cortical involvement signs with ataxia and DWI hyperintensity of the cerebral cortex on MRI. © 2016 Japanese Society of Neuropathology.

  9. Is brain copper deficiency in Alzheimer's, Lewy body, and Creutzfeldt Jakob diseases the common key for a free radical mechanism and oxidative stress-induced damage?

    PubMed

    Deloncle, Roger; Guillard, Olivier

    2015-01-01

    In Alzheimer's (AD), Lewy body (LBD), and Creutzfeldt Jakob (CJD) diseases, similar pathological hallmarks have been described, one of which is brain deposition of abnormal protease-resistant proteins. For these pathologies, copper bound to proteins is able to protect against free radicals by reduction from cupric Cu++ to cupreous Cu+. We have previously demonstrated in bovine brain homogenate that free radicals produce proteinase K-resistant prion after manganese is substituted for copper. Since low brain copper levels have been described in transmissible spongiform encephalopathies, in substantia nigra in Parkinson's disease, and in various brain regions in AD, LBD, and CJD, a mechanism has been proposed that may underlie the neurodegenerative processes that occur when copper protection against free radicals is impaired. In peptide sequences, the alpha acid proton near the peptide bond is highly mobile and can be pulled out by free radicals. It will produce a trivalent α-carbon radical and induce a free radical chain process that will generate a D-amino acid configuration in the peptide sequence. Since only L-amino acids are physiologically present in mammalian (human) proteins, it may be supposed that only physiological L-peptides can be recycled by physiological enzymes such as proteases. If a D-amino acid is found in the peptide sequence subsequent to deficient copper protection against free radicals, it will not be recognized and might alter the proteasome L-amino acid recycling from brain peptides. In the brain, there will result an accumulation of abnormal protease-resistant proteins such as those observed in AD, LBD, and CJD.

  10. Survival and re-operation rates after neurosurgical procedures in Scotland: implications for targeted surveillance of sub-clinical variant Creutzfeldt-Jakob disease.

    PubMed

    Bird, Sheila M; Merrall, Elizabeth L C; Ward, Hester J T; Will, Robert G

    2009-01-01

    To assess the feasibility of post-mortem surveillance for subclinical variant Creutzfeldt-Jakob disease (vCJD) at least 5 years after neurosurgical procedures. Using Scottish record linkage, we estimated 5-year survival and re-operation rates after 4 neurosurgical procedures performed during 1993-2001 and identified as high or medium risk for transmitting vCJD: [B] drainage of extra- or subdural haematoma, [E] primary or revisional decompression operations and [H] creation of other ventricular shunts were classified as high risk; [C] operations on cerebral aneurysm (clipping) were classified as medium risk. Fatality rate at 1 year depended strongly on procedure, weakly or not at all on sex and era, and increased with age. Procedure rates differed by sex. The rate of subsequent neurosurgical operations was highest for procedure [H] (sole: 21%; multiple: 28%). Each year, the UK has a new cohort of some 5,000 5-year survivors after a high- or medium-risk neurosurgical procedure, whose subsequent annual mortality is at least 3%. Even if half the surviving 5-year survivors of neurosurgery since 1996 gave consent-in-life for vCJD-informative testing at post-mortem, there would be too few relevant post-mortems in 2008-2010 (around 1,600) for 'nil detections' to exclude a 1 in 1,000 subclinical vCJD rate. Autopsy surveillance beyond 2010, or among 5-year survivors of non-neurosurgical at-risk operations, would be needed. (c) 2009 S. Karger AG, Basel.

  11. Rapid and Highly Sensitive Detection of Variant Creutzfeldt - Jakob Disease Abnormal Prion Protein on Steel Surfaces by Protein Misfolding Cyclic Amplification: Application to Prion Decontamination Studies

    PubMed Central

    Belondrade, Maxime; Nicot, Simon; Béringue, Vincent; Coste, Joliette; Lehmann, Sylvain; Bougard, Daisy

    2016-01-01

    The prevalence of variant Creutzfeldt-Jakob disease (vCJD) in the population remains uncertain, although it has been estimated that 1 in 2000 people in the United Kingdom are positive for abnormal prion protein (PrPTSE) by a recent survey of archived appendix tissues. The prominent lymphotropism of vCJD prions raises the possibility that some surgical procedures may be at risk of iatrogenic vCJD transmission in healthcare facilities. It is therefore vital that decontamination procedures applied to medical devices before their reprocessing are thoroughly validated. A current limitation is the lack of a rapid model permissive to human prions. Here, we developed a prion detection assay based on protein misfolding cyclic amplification (PMCA) technology combined with stainless-steel wire surfaces as carriers of prions (Surf-PMCA). This assay allowed the specific detection of minute quantities (10−8 brain dilution) of either human vCJD or ovine scrapie PrPTSE adsorbed onto a single steel wire, within a two week timeframe. Using Surf-PMCA we evaluated the performance of several reference and commercially available prion-specific decontamination procedures. Surprisingly, we found the efficiency of several marketed reagents to remove human vCJD PrPTSE was lower than expected. Overall, our results demonstrate that Surf-PMCA can be used as a rapid and ultrasensitive assay for the detection of human vCJD PrPTSE adsorbed onto a metallic surface, therefore facilitating the development and validation of decontamination procedures against human prions. PMID:26800081

  12. The reporting of theoretical health risks by the media: Canadian newspaper reporting of potential blood transmission of Creutzfeldt-Jakob disease

    PubMed Central

    Wilson, Kumanan; Code, Catherine; Dornan, Christopher; Ahmad, Nadya; Hébert, Paul; Graham, Ian

    2004-01-01

    Background The media play an important role at the interface of science and policy by communicating scientific information to the public and policy makers. In issues of theoretical risk, in which there is scientific uncertainty, the media's role as disseminators of information is particularly important due to the potential to influence public perception of the severity of the risk. In this article we describe how the Canadian print media reported the theoretical risk of blood transmission of Creutzfeldt-Jakob disease (CJD). Methods We searched 3 newspaper databases for articles published by 6 major Canadian daily newspapers between January 1990 and December 1999. We identified all articles relating to blood transmission of CJD. In duplicate we extracted information from the articles and entered the information into a qualitative software program. We compared the observations obtained from this content analysis with information obtained from a previous policy analysis examining the Canadian blood system's decision-making concerning the potential transfusion transmission of CJD. Results Our search identified 245 relevant articles. We observed that newspapers in one instance accelerated a policy decision, which had important resource and health implication, by communicating information on risk to the public. We also observed that newspapers primarily relied upon expert opinion (47 articles) as opposed to published medical evidence (28 articles) when communicating risk information. Journalists we interviewed described the challenges of balancing their responsibility to raise awareness of potential health threats with not unnecessarily arousing fear amongst the public. Conclusions Based on our findings we recommend that journalists report information from both expert opinion sources and from published studies when communicating information on risk. We also recommend researchers work more closely with journalists to assist them in identifying and appraising relevant

  13. Notification and support for people exposed to the risk of Creutzfeldt-Jakob disease (CJD) (or other prion diseases) through medical treatment (iatrogenically).

    PubMed

    Ryan, Rebecca; Hill, Sophie; Lowe, Dianne; Allen, Kelly; Taylor, Michael; Mead, Cathy

    2011-03-16

    Creutzfeldt-Jakob disease (CJD) and variant CJD (vCJD) are rare and always-fatal diseases transmissible via certain medical procedures. If a person is exposed to the disease risk through medical treatment, they may need to be notified of this to prevent them passing the risk to others in healthcare settings and to enable additional infection control measures to be put in place for certain procedures. As CJD is incurable, and unable to be screened for or effectively treated, communicating this risk information after an exposure incident may have significant implications for the person at risk, their families/ carers and healthcare professionals. The best ways to notify people of their exposure to the risk of CJD or vCJD, and to support them subsequently, are currently unknown. To evaluate the effects of interventions to notify and support consumers (patients and their family members or carers) in situations where exposure to the risk of CJD or vCJD has occurred as a result of medical treatment (iatrogenically), on consumer, healthcare provider and healthcare system outcomes. We searched the Cochrane Consumers and Communication Review Group Specialised Register (10 February, 2009), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1 2009), MEDLINE (OVID SP), EMBASE (OVID SP), PsycINFO (OVID SP), CINAHL (EBSCO Host), Current Contents (OVID SP) and Dissertation Abstracts (Proquest) from start date to February 2009. We searched MEDLINE In-process and Other Non-indexed Citations (OVID SP) and Sociological Abstracts (CSA) in November 2009. We searched reference lists, websites, and contacted consumer groups and experts for details of relevant research. Randomised and quasi-randomised controlled studies, controlled before-and-after studies and interrupted time series analyses assessing the effects of any intervention to communicate with (notify or support) people exposed to the risk of CJD or vCJD through medical treatment were

  14. Panencephalopathic Creutzfeldt-Jakob disease with distinct pattern of prion protein deposition in a patient with D178N mutation and homozygosity for valine at codon 129 of the prion protein Gene.

    PubMed

    Marcon, Gabriella; Indaco, Antonio; Di Fede, Giuseppe; Suardi, Silvia; Finato, Nicoletta; Moretti, Valentino; Micoli, Sandro; Fociani, Paolo; Zerbi, Pietro; Pincherle, Alessandro; Redaelli, Veronica; Tagliavini, Fabrizio; Giaccone, Giorgio

    2014-03-01

    Prion diseases include sporadic, acquired and genetic forms linked to mutations of the prion protein (PrP) gene (PRNP). In subjects carrying the D178N PRNP mutation, distinct phenotypes can be observed, depending on the methionine/valine codon 129 polymorphism. We present here a 53-year-old woman with D178N mutation in the PRNP gene and homozygosity for valine at codon 129. The disease started at age 47 with memory deficits, progressive cognitive impairment and ataxia. The clinical picture slowly worsened to a state of akinetic mutism in about 2 years and the disease course was 6 years. The neuropathologic examination demonstrated severe diffuse cerebral atrophy with neuronal loss, spongiosis and marked myelin loss and tissue rarefaction in the hemispheric white matter, configuring panencephalopathic Creutzfeldt-Jakob disease. PrP deposition was present in the cerebral cortex, basal ganglia and cerebellum with diffuse synaptic-type pattern of immunoreactivity and clusters of countless, small PrP deposits, particularly evident in the lower cortical layers, in the striatum and in the molecular layer of the cerebellum. Western blot analysis showed the presence of type 1 PrP(Sc) (Parchi classification). These findings underline the clear-cut distinction between the neuropathological features of Creutzfeldt-Jakob disease associated with D178N PRNP mutation and those of fatal familial insomnia.

  15. Roles of methionine oxidation in E200K prion protein misfolding: Implications for the mechanism of pathogenesis in E200K linked familial Creutzfeldt-Jakob disease.

    PubMed

    Wang, Zonglin; Feng, Boya; Xiao, Gengfu; Zhou, Zheng

    2016-04-01

    Prion diseases are a group of neurodegenerative diseases caused by prion protein (PrP) conformational changes. More than 30 PRNP gene mutations have been associated with familial prion diseases. E200K-associated familial Creutzfeldt-Jakob disease (fCJD) is the most common inherited prion disease. One of the hallmarks of prion diseases is the accumulation of oxidative damage. The mechanism by which oxidative modification of methionine (Met) residues influence the E200K PrP misfolding remains unclear. Here, we examined the stability, structural change, oligomerization and proteinase K resistance of unoxidized/oxidized E200K PrP and Met-to-Leu mutants. We found that oxidation of surface-exposed Met109/112/129/134/154/166 residues significantly destabilized E200K PrP but had a limited impact on the protein's structure. The oxidation of Met213 was the initial step in the conformational conversion of E200K PrP and facilitated the further oxidation of Met205/206. The oxidation of Met213/205/206 led to the exposure of the inner hydrophobic core, disrupted the overall structure of E200K PrP and induced the formation of large soluble multimers at low pH. In addition, the aggregation behavior of oxidized E200K PrP at the cellular level was investigated using E200K PrP Met-to-Ser mutants. The results showed that M109/112/129/154S or M134/166S mutants were efficiently localized on the cell membrane, whereas the M213/205/206S mutant generated many of aggregated fluorescent dots in the cytoplasm. The present work provides important clues for understanding the special roles of methionine oxidation in E200K PrP misfolding and links oxidative stress and consequent misfolding of oxidative damaged E200K PrP with the pathogenic mechanism of E200K-associated fCJD. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent.

    USGS Publications Warehouse

    Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

    2013-01-01

    Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in v

  17. Red-Backed Vole Brain Promotes Highly Efficient In Vitro Amplification of Abnormal Prion Protein from Macaque and Human Brains Infected with Variant Creutzfeldt-Jakob Disease Agent

    PubMed Central

    Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

    2013-01-01

    Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in vCJD-infected human

  18. Deciphering the pathogenesis of sporadic Creutzfeldt-Jakob disease with codon 129 M/V and type 2 abnormal prion protein

    PubMed Central

    2013-01-01

    Background Sporadic Creutzfeldt-Jakob disease is classified according to the genotype at polymorphic codon 129 (M or V) of the prion protein (PrP) gene and the type (1 or 2) of abnormal isoform of PrP (PrPSc) in the brain. The most complicated entity in the current classification system is MV2, since it shows wide phenotypic variations, i.e., MV2 cortical form (MV2C), MV2 with kuru plaques (MV2K), or a mixed form (MV2K + C). To resolve their complicated pathogenesis, we performed a comprehensive analysis of the three MV2 subgroups based on histopathological, molecular, and transmission properties. Results In histopathological and molecular analyses, MV2C showed close similarity to MM2 cortical form (MM2C) and could be easily discriminated from the other MV2 subgroups. By contrast, MV2K and MV2K + C showed the same molecular type and the same transmission type, and the sole difference between MV2K and MV2K + C was the presence of cortical pathology characteristic of MV2C/MM2C. The remarkable molecular feature of MV2K or MV2K + C was a mixture of type 2 PrPSc and intermediate type PrPSc, which shows intermediate electrophoretic mobility between types 1 and 2 PrPSc. Modeling experiments using PrP-humanized mice indicated that MV2K contains a mixture of intermediate type PrPSc with the 129M genotype (Mi PrPSc) and type 2 PrPSc with the 129V genotype (V2 PrPSc) that originated from V2 PrPSc, whereas MV2C + K may also contain type 2 PrPSc with the 129M genotype and cortical pathology (M2C PrPSc) that lacks infectivity to the PrP-humanized mice in addition to Mi and V2 PrPSc. Conclusions Taken together, the present study suggests that the phenotypic heterogeneity of MV2 stems from their different PrPSc origin(s). PMID:24252157

  19. Absence of Evidence for a Causal Link between Bovine Spongiform Encephalopathy Strain Variant L-BSE and Known Forms of Sporadic Creutzfeldt-Jakob Disease in Human PrP Transgenic Mice.

    PubMed

    Jaumain, Emilie; Quadrio, Isabelle; Herzog, Laetitia; Reine, Fabienne; Rezaei, Human; Andréoletti, Olivier; Laude, Hubert; Perret-Liaudet, Armand; Haïk, Stéphane; Béringue, Vincent

    2016-12-01

    Prions are proteinaceous pathogens responsible for subacute spongiform encephalopathies in animals and humans. The prions responsible for bovine spongiform encephalopathy (BSE) are zoonotic agents, causing variant Creutzfeldt-Jakob disease (CJD) in humans. The transfer of prions between species is limited by a species barrier, which is thought to reflect structural incompatibilities between the host cellular prion protein (PrP(C)) and the infecting pathological PrP assemblies (PrP(Sc)) constituting the prion. A BSE strain variant, designated L-BSE and responsible for atypical, supposedly spontaneous forms of prion diseases in aged cattle, demonstrates zoonotic potential, as evidenced by its capacity to propagate more easily than classical BSE in transgenic mice expressing human PrP(C) and in nonhuman primates. In humanized mice, L-BSE propagates without any apparent species barrier and shares similar biochemical PrP(Sc) signatures with the CJD subtype designated MM2-cortical, thus opening the possibility that certain CJD cases classified as sporadic may actually originate from L-type BSE cross-transmission. To address this issue, we compared the biological properties of L-BSE and those of a panel of CJD subtypes representative of the human prion strain diversity using standard strain-typing criteria in human PrP transgenic mice. We found no evidence that L-BSE causes a known form of sporadic CJD. Since the quasi-extinction of classical BSE, atypical BSE forms are the sole BSE variants circulating in cattle worldwide. They are observed in rare cases of old cattle, making them difficult to detect. Extrapolation of our results suggests that L-BSE may propagate in humans as an unrecognized form of CJD, and we urge both the continued utilization of precautionary measures to eliminate these agents from the human food chain and active surveillance for CJD phenotypes in the general population. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  20. MM1-type sporadic Creutzfeldt-Jakob disease with 1-month total disease duration and early pathologic indicators.

    PubMed

    Iwasaki, Yasushi; Kato, Hiroko; Ando, Tetsuo; Mimuro, Maya; Kitamoto, Tetsuyuki; Yoshida, Mari

    2017-04-12

    A 62-year-old man presented with abnormal behavior and cognitive impairment. Diffusion-weighted images (DWI) obtained on MRI showed extensive hyperintense regions in the cerebral cortex and striatum. Myoclonus was recognized, and the patient died 1 month after the onset; his condition did not reach the akinetic mutism state. The brain weighed 1300 g and showed no apparent atrophy. Extensive spongiform changes were observed in the cerebral neocortex, striatum, thalamus and cerebellar cortex, but gliosis was mild or absent. Neuropil rarefaction and neuron loss were not apparent. Mild proliferation of anti- GFAP-positive astrocytes was observed in the cerebral cortex, but unaffected regions were noted. Regions without spongiform changes and GFAP-positive astrocytes included the hippocampal formation and subiculum. PrP immunostaining showed extensive diffuse synaptic-type PrP deposition in the gray matter, including the hippocampal region, but it was also mild. PrP gene analysis revealed no mutation with methionine homozygosity at polymorphic codon 129. Western blot analysis of proteinase K-resistant PrP indicated type 1 PrP(Sc) . The clinicopathological findings of the present case confirm several hypotheses: (i) the earliest pathologic evidence observed by HE staining in CJD are spongiform changes; (ii) DWI hyperintense regions indicate these spongiform changes; and (iii) regions without spongiform changes, gliosis and proliferation of GFAP-positive astrocytes, but with PrP deposition, exist in the early disease stage.

  1. Public health issues and clinical and neurological characteristics of the new variant of Creutzfeldt-Jakob disease and other human and animal transmissible spongiform encephalopathies: memorandum from two WHO meetings.

    PubMed Central

    1996-01-01

    The transmissible spongiform encephalopathies (TSEs) include bovine spongiform encephalopathy (BSE), which was first described in 1986 in cattle in the United Kingdom, but has occurred subsequently also in other countries, and Creutzfeldt-Jakob disease (CJD) in humans, which is rare but with a worldwide distribution. Recently a new variant form of CJD, with a characteristic clinical and pathological phenotype, has been identified in the United Kingdom in a series of 11 young patients. This Memorandum reports the findings of two WHO Consultations. The first, held on 2-3 April 1996, issued conclusions and recommendations on certain animal products in order to protect the health of consumers. The second, held on 14-16 May 1996, examined, inter alia, the findings associated with the new variant of CJD, compared these findings with those for other TSEs, and proposed a protocol for the diagnosis and surveillance of CJD and related diseases. PMID:9002325

  2. Gerstmann-Sträussler-Scheinker syndrome with the P102L pathogenic mutation presenting as familial Creutzfeldt-Jakob disease: a case report and review of the literature.

    PubMed

    Rusina, Robert; Fiala, Jindřich; Holada, Karel; Matějčková, Milada; Nováková, Jana; Ampapa, Radek; Koukolík, František; Matěj, Radoslav

    2013-01-01

    Gerstmann-Sträussler-Scheinker syndrome is a rare autosomal dominant disease caused by a mutation in the prion gene, usually manifesting as progressive ataxia with late cognitive decline. A 44-year-old woman with a positive family history developed early personality and behavior changes, followed by paresthesias and ataxia, later associated with memory problems, pyramidal signs, anosognosia and very late myoclonus, spasticity, and severe dysexecutive impairment. Magnetic resonance showed caudate, mesio-frontal, and insular hyper-intensities, electroencephalography revealed generalized triphasic periodic complexes. A pathogenic P102L mutation in the prion gene was detected. Our case differed from classical Gerstmann-Sträussler-Scheinker syndrome by rapid progression, severe dementia, abnormal electroencephalography and magnetic resonance findings, which were highly suggestive of familial Creutzfeldt-Jakob disease.

  3. Generalized cerebral atrophy seen on MRI in a naturally exposed animal model for creutzfeldt-jakob disease

    PubMed Central

    2010-01-01

    Background Magnetic resonance imaging has been used in the diagnosis of human prion diseases such as sCJD and vCJD, but patients are scanned only when clinical signs appear, often at the late stage of disease. This study attempts to answer the questions "Could MRI detect prion diseases before clinical symptoms appear?, and if so, with what confidence?" Methods Scrapie, the prion disease of sheep, was chosen for the study because sheep can fit into a human sized MRI scanner (and there were no large animal MRI scanners at the time of this study), and because the USDA had, at the time of the study, a sizeable sample of scrapie exposed sheep, which we were able to use for this purpose. 111 genetically susceptible sheep that were naturally exposed to scrapie were used in this study. Results Our MRI findings revealed no clear, consistent hyperintense or hypointense signal changes in the brain on either clinically affected or asymptomatic positive animals on any sequence. However, in all 37 PrPSc positive sheep (28 asymptomatic and 9 symptomatic), there was a greater ventricle to cerebrum area ratio on MRI compared to 74 PrPSc negative sheep from the scrapie exposed flock and 6 control sheep from certified scrapie free flocks as defined by immunohistochemistry (IHC). Conclusions Our findings indicate that MRI imaging can detect diffuse cerebral atrophy in asymptomatic and symptomatic sheep infected with scrapie. Nine of these 37 positive sheep, including 2 one-year old animals, were PrPSc positive only in lymph tissues but PrPSc negative in the brain. This suggests either 1) that the cerebral atrophy/neuronal loss is not directly related to the accumulation of PrPSc within the brain or 2) that the amount of PrPSc in the brain is below the detectable limits of the utilized immunohistochemistry assay. The significance of these findings remains to be confirmed in human subjects with CJD. PMID:21108848

  4. R3-R4 deletion in the PRNP gene is associated with Creutzfeldt-Jakob disease (CJD)

    SciTech Connect

    Cervenakova, L.; Brown, P.; Nagle, J.

    1994-09-01

    There are conflicting reports on the association of deletions in the PRNP gene on chromosome 20 with CJD, a rapidly progressive fatal spongiform encephalopathy. We accumulated data suggesting that a deletion of R3-R4 type (parts of the third and fourth repeats are deleted from the area of four repeating 24 bp sequences in the 5{prime} region of the gene) is causing CJD. Screening of 129 unaffected control individuals demonstrated presence of a deletion of R2 type in four (1.55% of the studied chromosomes), but none of them had the R3-R4 type. Of 181 screened patients with spongiform encephalopathies, two had a deletion of R3-R4 type with no other mutations in the coding sequence. Both patients had a classical rapidly progressive dementing disease and diffuse spongiform degeneration, and both cases were apparently sporadic. The same R3-R4 type of deletion was detected in three additional neuropathologically confirmed spongiform encephalopathy patients, of which two had other known pathogenic mutations in the PRNP gene: at codon 178 on the methionine allele exhibiting the phenotype of fatal familial insomnia, and codon 200 causing CJD with severe dementia; the third was a patient with iatrogenic CJD who developed the disease after treatment with growth hormone extracted from cadaveric human pituitary glands. In all cases the deletion coincided with a variant sequence at position 129 coding for methionine.

  5. Stability and Reproducibility Underscore Utility of RT-QuIC for Diagnosis of Creutzfeldt-Jakob Disease.

    PubMed

    Cramm, Maria; Schmitz, Matthias; Karch, André; Mitrova, Eva; Kuhn, Franziska; Schroeder, Bjoern; Raeber, Alex; Varges, Daniela; Kim, Yong-Sun; Satoh, Katsuya; Collins, Steven; Zerr, Inga

    2016-04-01

    Real-time quaking-induced conversion (RT-QuIC) allows the amplification of miniscule amounts of scrapie prion protein (PrP(Sc)). Recent studies applied the RT-QuIC methodology to cerebrospinal fluid (CSF) for diagnosing human prion diseases. However, to date, there has not been a formal multi-centre assessment of the reproducibility, validity and stability of RT-QuIC in this context, an indispensable step for establishment as a diagnostic test in clinical practice. In the present study, we analysed CSF from 110 prion disease patients and 400 control patients using the RT-QuIC method under various conditions. In addition, "blinded" ring trials between different participating sites were performed to estimate reproducibility. Using the previously established cut-off of 10,000 relative fluorescence units (rfu), we obtained a sensitivity of 85% and a specificity of 99%. The multi-centre inter-laboratory reproducibility of RT-QuIC revealed a Fleiss' kappa value of 0.83 (95% CI: 0.40-1.00) indicating an almost perfect agreement. Moreover, we investigated the impact of short-term CSF storage at different temperatures, long-term storage, repeated freezing and thawing cycles and the contamination of CSF with blood on the RT-QuIC seeding response. Our data indicated that the PrP(Sc) seed in CSF is stable to any type of storage condition but sensitive to contaminations with blood (>1250 erythrocytes/μL), which results in a false negative RT-QuIC response. Fresh blood-contaminated samples (3 days) can be rescued by removal of erythrocytes. The present study underlines the reproducibility and high stability of RT-QuIC across various CSF storage conditions with a remarkable sensitivity and specificity, suggesting RT-QuIC as an innovative and robust diagnostic method.

  6. First demonstration of transmissible spongiform encephalopathy-associated prion protein (PrPTSE) in extracellular vesicles from plasma of mice infected with mouse-adapted variant Creutzfeldt-Jakob disease by in vitro amplification.

    PubMed

    Saá, Paula; Yakovleva, Oksana; de Castro, Jorge; Vasilyeva, Irina; De Paoli, Silvia H; Simak, Jan; Cervenakova, Larisa

    2014-10-17

    The development of variant Creutzfeldt-Jakob disease (vCJD) in three recipients of non-leukoreduced red blood cells from asymptomatic donors who subsequently developed the disease has confirmed existing concerns about the possible spread of transmissible spongiform encephalopathies (TSEs) via blood products. In addition, the presence of disease-associated misfolded prion protein (PrP(TSE)), generally associated with infectivity, has been demonstrated in the blood of vCJD patients. However, its origin and distribution in this biological fluid are still unknown. Various studies have identified cellular prion protein (PrP(C)) among the protein cargo in human blood-circulating extracellular vesicles released from endothelial cells and platelets, and exosomes isolated from the conditioned media of TSE-infected cells have caused the disease when injected into experimental mice. In this study, we demonstrate the detection of PrP(TSE) in extracellular vesicles isolated from plasma samples collected during the preclinical and clinical phases of the disease from mice infected with mouse-adapted vCJD and confirm the presence of the exosomal marker Hsp70 in these preparations. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. First Demonstration of Transmissible Spongiform Encephalopathy-associated Prion Protein (PrPTSE) in Extracellular Vesicles from Plasma of Mice Infected with Mouse-adapted Variant Creutzfeldt-Jakob Disease by in Vitro Amplification*

    PubMed Central

    Saá, Paula; Yakovleva, Oksana; de Castro, Jorge; Vasilyeva, Irina; De Paoli, Silvia H.; Simak, Jan; Cervenakova, Larisa

    2014-01-01

    The development of variant Creutzfeldt-Jakob disease (vCJD) in three recipients of non-leukoreduced red blood cells from asymptomatic donors who subsequently developed the disease has confirmed existing concerns about the possible spread of transmissible spongiform encephalopathies (TSEs) via blood products. In addition, the presence of disease-associated misfolded prion protein (PrPTSE), generally associated with infectivity, has been demonstrated in the blood of vCJD patients. However, its origin and distribution in this biological fluid are still unknown. Various studies have identified cellular prion protein (PrPC) among the protein cargo in human blood-circulating extracellular vesicles released from endothelial cells and platelets, and exosomes isolated from the conditioned media of TSE-infected cells have caused the disease when injected into experimental mice. In this study, we demonstrate the detection of PrPTSE in extracellular vesicles isolated from plasma samples collected during the preclinical and clinical phases of the disease from mice infected with mouse-adapted vCJD and confirm the presence of the exosomal marker Hsp70 in these preparations. PMID:25157106

  8. An autopsy-verified case of FTLD-TDP type A with upper motor neuron-predominant motor neuron disease mimicking MM2-thalamic-type sporadic Creutzfeldt-Jakob disease.

    PubMed

    Hayashi, Yuichi; Iwasaki, Yasushi; Takekoshi, Akira; Yoshikura, Nobuaki; Asano, Takahiko; Mimuro, Maya; Kimura, Akio; Satoh, Katsuya; Kitamoto, Tetsuyuki; Yoshida, Mari; Inuzuka, Takashi

    2016-11-01

    Here we report an autopsy-verified case of frontotemporal lobar degeneration (FTLD)-transactivation responsive region (TAR) DNA binding protein (TDP) type A with upper motor neuron-predominant motor neuron disease mimicking MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD). A 69-year-old woman presented with an 11-month history of progressive dementia, irritability, insomnia, and gait disturbance without a family history of dementia or prion disease. Neurological examination revealed severe dementia, frontal signs, and exaggerated bilateral tendon reflexes. Periodic sharp-wave complexes were not observed on the electroencephalogram. Brain diffusion MRI did not reveal abnormal changes. An easy Z score (eZIS) analysis for (99m)Tc-ECD-single photon emission computed tomography ((99m)Tc-ECD-SPECT) revealed a bilateral decrease in thalamic regional cerebral blood flow (rCBF). PRNP gene analysis demonstrated methionine homozygosity at codon 129 without mutation. Cerebrospinal fluid (CSF) analysis showed normal levels of both 14-3-3 and total tau proteins. Conversely, prion protein was slowly amplified in the CSF by a real-time quaking-induced conversion assay. Her symptoms deteriorated to a state of akinetic mutism, and she died of sudden cardiac arrest, one year after symptom onset.  Despite the SPECT results supporting a clinical diagnosis of MM2-thalamic-type sCJD, a postmortem assessment revealed that this was a case of FTLD-TDP type A, and excluded prion disease. Thus, this case indicates that whereas a bilateral decreasing thalamic rCBF detected by (99m)Tc-ECD-SPECT can be useful for diagnosing MM2-thalamic-type sCJD, it is not sufficiently specific. Postmortem diagnosis remains the gold standard for the diagnosis of this condition.

  9. An autopsied case of MM1 + MM2-cortical with thalamic-type sporadic Creutzfeldt-Jakob disease presenting with hyperintensities on diffusion-weighted MRI before clinical onset.

    PubMed

    Iwasaki, Yasushi; Mori, Keiko; Ito, Masumi; Mimuro, Maya; Kitamoto, Tetsuyuki; Yoshida, Mari

    2017-02-01

    + MM2-cortical with thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD), which suggests a broader spectrum of sCJD clinicopathological findings. © 2016 Japanese Society of Neuropathology.

  10. Diagnostic Accuracy of a Combined Analysis of Cerebrospinal Fluid t-PrP, t-tau, p-tau, and Aβ42 in the Differential Diagnosis of Creutzfeldt-Jakob Disease from Alzheimer’s Disease with Emphasis on Atypical Disease Variants

    PubMed Central

    Abu Rumeileh, Samir; Lattanzio, Francesca; Stanzani Maserati, Michelangelo; Rizzi, Romana; Capellari, Sabina; Parchi, Piero

    2016-01-01

    According to recent studies, the determination of cerebrospinal fluid (CSF) total tau (t-tau)/phosphorylated tau (p-tau) ratio and total prion protein (t-PrP) levels significantly improves the accuracy of the diagnosis of Alzheimer’s disease (AD) in atypical cases with clinical or laboratory features mimicking Creutzfeldt-Jakob disease (CJD). However, this has neither been validated nor tested in series including atypical CJD variants. Furthermore, the added diagnostic value of amyloid-β (Aβ)42 remains unclear. To address these issues, we measured t-PrP, 14-3-3, t-tau, p-tau, and Aβ42 CSF levels in 45 typical and 44 atypical/rapidly progressive AD patients, 54 typical and 54 atypical CJD patients, and 33 controls. CJD patients showed significantly lower CSF t-PrP levels than controls and AD patients. Furthermore, atypical CJD was associated with lower t-PrP levels in comparison to typical CJD. T-tau, 14-3-3, or t-PrP alone yielded, respectively, 80.6, 63.0, and 73.0% sensitivity and 75.3, 92.1, and 75% specificity in distinguishing AD from CJD. On receiver operating characteristic (ROC) curve analyses of biomarker combinations, the (t-tau×Aβ42)/(p-tau×t-PrP) ratio achieved the best accuracy, with 98.1% sensitivity and 97.7% specificity overall, and 96.2% sensitivity and 95.5% specificity for the “atypical” disease groups. Our results show that the combined analysis of CSF t-PrP, t-tau, p-tau, and Aβ42 is clinically useful in the differential diagnosis between CJD and AD. Furthermore, the finding of reduced CSF t-PrP levels in CJD patients suggest that, likewise Aβ42 in AD, CSF t-PrP levels reflect the extent of PrPc conversion into abnormal PrP (PrPSc) and the burden of PrPSc deposition in CJD. PMID:27886009

  11. Creutzfeldt-Jakob disease-like periodic sharp wave complexes in voltage-gated potassium channel-complex antibodies encephalitis : A Case Report

    PubMed Central

    Savard, Martin; Irani, Sarosh R.; Guillemette, Annie; Gosselin-Lefebvre, Stéphanie; Geschwind, Michael; Jansen, Gerard H.; Gould, Peter V.; Laforce, Robert

    2015-01-01

    Introduction Voltage-gated potassium channel-complex antibodies (VGKC-cAbs) encephalitis, a treatable autoantibody encephalopathy, has been previously reported to clinically mimic sporadic Creutzfeldt-Jacob disease (sCJD). Among available clinical clues to distinguish them, periodic sharp wave complexes (PSWC), a typical finding in sCJD, have never been reported in association with VGKC-cAbs encephalitis. Case presentation A 76 years old man was transferred to a tertiary neurology center with a clinical history of six-month weight loss, cognitive disturbance and non specific generalized weakness. He had two seizures the month before transfer and then evolved to severe encephalopathy, requiring mechanical ventilation. PSWC every 1–2 seconds over slowed background were found on EEG, and MRI showed cerebellar and bifrontal cortical T2/FLAIR/DWI hypersignal without restricted diffusion on ADC mapping. Pancorporal PET-scan was negative. An immunotherapy trial did not improve the patient condition. Therefore, he died after life support withdrawal. Brain autopsy revealed mononuclear neocortex infiltrate without significant spongiosis, and the anti-VGKC test showed a seropositivity of 336 pmol/L (normal: 0–31), three month after the patient deceased. Conclusion This is the first reported case of VGKC-cAbs encephalitis associated with PSWC on EEG, which further confuse the differential diagnosis with sCJD. However, the cortical DWI hypersignal without restriction seem to remain a way to discriminate these two entities appropriately, when present. These clues are of paramount importance since VGKC-cAbs encephalitis is a treatable disease. PMID:26375660

  12. An autopsied case of Creutzfeldt-Jakob disease with mutation in the prion protein gene codon 232 and type 1+2 prion protein.

    PubMed

    Iwasaki, Yasushi; Yokoi, Fuji; Tatsumi, Shinsui; Mimuro, Maya; Iwai, Katsushige; Kitamoto, Tetsuyuki; Yoshida, Mari

    2013-10-01

    A 68-year-old Japanese man gradually showed abnormal behavior and gait disturbance with bradykinesia. Slowly progressive dementia, including memory disturbance and disorientation, was also observed. Cerebral cortical hyperintensity on diffusion-weighted MRI was observed 6 months after onset. The patient progressed to an akinetic mutism state with mild myoclonus, and atypical periodic sharp-wave complexes were observed by electroencephalogram 13 months after onset. He was clinically suspected of having atypical CJD and died after 19 months total disease duration. The brain weighed 1160 g and showed mild atrophy of the cerebrum and cerebellum with ventricular dilatation. Spongiform changes with varying vacuole size and gliosis was extensive in the cerebral cortex and basal ganglia. Neuron loss in the cerebral cortex, basal ganglia and thalamus was relatively mild. The cerebellum showed mild spongiform changes of the molecular layer and mild neuron loss in the Purkinje cell layer. PrP immunostaining showed mainly coarse-type combined with diffuse synaptic-type PrP deposition in the cerebral gray matter. Some perivacuolar-type PrP deposition was also present. Numerous plaque-type PrP depositions were observed in the molecular layer of the cerebellum. Analysis of the PrP gene revealed a methionine-to-arginine (Met-to-Arg) substitution at codon 232 (M232R) with Met homozygosity at codon 129. Western blot analysis of protease-resistant PrP indicated type 2 dominant PrP combined with type 1. Genetic CJD with M232R substitution in the PrP gene has only been reported in Japan. Although two clinical phenotypes (rapid-type and slow-type) were suggested in the M232R CJD cases (despite the presence of the same PrP genotype), the pathological and molecular backgrounds have not been well understood because there have only been a few autopsied case reports. This is the first case report of M232R CJD presenting with 1 + 2 PrP.

  13. Hashimoto's encephalopathy mimicking Creutzfeldt-Jakob disease.

    PubMed

    Gauthier, Angela C; Baehring, Joachim M

    2017-01-01

    Hashimoto's encephalopathy is a rare, imprecisely defined autoimmune neurologic syndrome associated with Hashimoto's thyroiditis that normally responds to corticosteroids. Here, we describe the case of a 55-year-old woman who presented with subacute cognitive decline and ataxia. Neoplastic, paraneoplastic, infectious, and metabolic etiologies were ruled out. Anti-TPO antibody level was markedly elevated at 966U/mL. After one month of 60mg/day of oral prednisone, she felt back to baseline and her Montreal Cognitive Assessment dramatically improved. Physicians should strongly consider this uncommon diagnosis in patients with rapid cognitive decline and no other clear etiology.

  14. Decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata determined by an easy Z-score (eZIS) analysis of (99m)Tc-ECD-SPECT images in a case of MM2-thalamic-type sporadic Creutzfeldt-Jakob disease.

    PubMed

    Hayashi, Yuichi; Iwasaki, Yasushi; Yoshikura, Nobuaki; Asano, Takahiko; Hatano, Taku; Tatsumi, Shinsui; Satoh, Katsuya; Kimura, Akio; Kitamoto, Tetsuyuki; Yoshida, Mari; Inuzuka, Takashi

    2015-11-15

    We report a case of autopsy-verified MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD) in a 46-year-old patient with a 16-month history of abnormal behavior, progressive dementia, insomnia, and speech disturbances without family history. Neurological examination revealed progressive dementia, frontal signs, insomnia, speech disturbance, gait disturbance and bilaterally exaggerated tendon reflexes. Both brain MRI and cerebrospinal fluid examinations, including 14-3-3 protein, yielded normal results. An easy Z-score (eZIS) analysis for (99m)Tc-ethyl cysteinate dimer-single photon emission computed tomography ((99m)Tc-ECD-SPECT) revealed decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata. PRNP gene analysis revealed methionine homozygosity at codon 129 without mutation. Neuropathological examinations revealed severe neuronal loss, gliosis, and hypertrophic astrocytosis in the medial thalamus and inferior olivary nucleus. A slight depletion of Purkinje cells was observed. PrP immunostaining showed no obvious PrP deposits in the basal ganglia, thalamus, cerebellum, or brainstem; however, mild synaptic-type PrP deposits with some smaller plaque-like structures were only partially observed in the localized region of the frontal lobe with the spongiform change. Western blot analyses of protease-resistant PrP showed a type 2 pattern. In conclusion, eZIS analysis of (99m)Tc-ECD-SPECT images is useful for detecting both thalamic and medullary lesions. This is the first case of medullary lesions detected in a live patient with MM2-thalamic-type sCJD using SPECT.

  15. Coexistence of mixed phenotype Creutzfeldt-Jakob disease, Lewy body disease and argyrophilic grain disease plus histological features of possible Alzheimer's disease: a multi-protein disorder in an autopsy case.

    PubMed

    Fernández-Vega, Iván; Ruiz-Ojeda, Javier; Juste, Ramon A; Geijo, Maria; Zarranz, Juan Jose; Sánchez Menoyo, Jose Luis; Vicente-Etxenausia, Ikerne; Mediavilla-García, Jennifer; Guerra-Merino, Isabel

    2015-02-01

    We report hereby an autopsy case of sporadic mixed phenotype CJD without hereditary burden and a long-term clinical course. An 80-year old man was diagnosed with mild cognitive impairment 27 months before death, caused by bronchopneumonia and severe respiratory impairment. During this time, the patient developed gradual mental deterioration, some sleeping problems and myoclonus. Other clinical manifestations were progressive gait problems, language deterioration, presence of primitive reflexes and irritability. In keeping with those symptoms, a rapidly evolving dementia was clinically suspected. Cerebrospinal fluid test for 14-3-3 protein was negative. However, an abnormal EEG and MRI at end-stage of disease were finally consistent with CJD. Post-mortem examination revealed a massive cortical neuronal loss with associated reactive astrocytosis, also evident in the white matter. Diffuse spongiform changes involving some basal ganglia, especially medial thalamus, some troncoencephalic nuclei, mainly inferior olivary nucleus and the molecular layer of the cerebellum were seen. Immunorreactive deposits for anti-prion protein antibody were present at different areas of the CNS. Additionally, Lewy bodies were observed at the brainstem and amygdala. Furthermore, argirophilic grains together with oligodendroglial coiled bodies and pre-tangle inclusions in the neurons from the limbic system containing hyperphosphorylated 4R tau were noted. To the best of our knowledge, this is the first case of CJD combined with Lewy body disease and argirophilic grain disease. Furthermore, we believe this case is an extremely rare combination of MM2-cortical-type and MM2-thalamic-type sporadic CJD (sCJD), which explains the broad spectrum of MM2-type sCJD findings and symptoms. Moreover, histological features of possible Alzheimer's disease were also reported.

  16. Cleanability of dental instruments--implications of residual protein and risks from Creutzfeldt-Jakob disease.

    PubMed

    Walker, J T; Dickinson, J; Sutton, J M; Raven, N D H; Marsh, P D

    2007-10-13

    Cleaning of dental instruments is the first line of control in reducing the adherent bioburden. The threat of vCJD and the difficulty in removing prion protein has provided a new challenge for cleaning surgical and dental instruments. Prion proteins are also more resistant to many disinfection and sterilisation techniques. A number of different methods are currently available in primary care for cleaning instruments including manual washing, ultrasonic cleaners and washer disinfectors. Manual cleaning of dental instruments is time-consuming, introduces operator error and the risk of puncture wounds, is not reproducible and does not completely remove debris from instruments. Ultrasonic baths are significantly more effective than hand cleaning alone and are currently used by the majority of dental surgeries (often as an adjunct to manual cleaning). Automated washer-disinfectors appear to provide a validated, reliable and reproducible procedure for disinfection and sterilisation of dental instruments to ensure both the safety of patients and dental staff. Dental instruments that are difficult to clean are frequently contaminated with tissue debris after routine reprocessing and cannot be excluded as a potential transmission risk for infectious agents, including prions. The transmission of vCJD via dentistry is considered to be low risk, however, the Department of Health (DoH) has recently advised dentists to ensure that endodontic reamers and files are treated as single-use as a precautionary basis in order to further reduce any risk of vCJD transmission.

  17. MM1+2C sporadic Creutzfeldt-Jakob disease presenting as rapidly progressive nonfluent aphasia.

    PubMed

    Allegri, Ricardo F; Bartoloni, Leonardo; Iturry, Mónica; Romero, Carlos; Begué, Christián; Sevlever, Gustavo; Taratuto, Ana Lía

    2014-01-01

    We report a 77-year-old man, presenting with progressive aphasia as an initial symptom, who developed severe dementia over the course of 20 months. Frontal cortex PrPSc western blot was type 2 and codon 129 was MM; brain neuropathology showed cortical vacuoles with perivacuolar PrP immunostaining characteristic of MM2C. Cerebellum showed focal coarse, patchy staining in different sections of the molecular layer, diffuse fine punctuate and coarse PrP immunopositive deposits in the granule cell layer, and focal synaptic immunostaining in the molecular layer, suggestive of MM1+2C by histotyping. This clinical presentation has not yet been described in an MM1+2C subtype by histotyping.

  18. Prion diseases: New considerations.

    PubMed

    Annus, Ádám; Csáti, Anett; Vécsei, László

    2016-11-01

    The transmissible spongiform encephalopathies, which include Creutzfeldt-Jakob disease, are fatal neurodegenerative disorders caused by the pathological accumulation of abnormal prion protein. The diagnosis of Creutzfeldt-Jakob disease is complex. The electroencephalogram, magnetic resonance imaging, lumbar puncture and genetic testing findings can help in the differential diagnosis of rapidly progressive dementia. There has recently been considerable debate as to whether proteins involved in the development of neurodegenerative diseases should be regarded as prions or only share prion-like mechanisms. Two recent reports described the detection of abnormal prion protein in the nasal mucosa and urine of patients with Creutzfeldt-Jakob disease. These findings raise major health concerns regarding the transmissibility of human prion diseases. We set out to address this neurological hot topic and to draw conclusions on the basis of what is known in the literature thus far.

  19. Quantitative EEG parameters correlate with the progression of human prion diseases

    PubMed Central

    Wehner, Tim; Lowe, Jessica; Porter, Marie-Claire; Kenny, Joanna; Thompson, Andrew; Rudge, Peter; Collinge, John; Mead, Simon

    2016-01-01

    Background Prion diseases are universally fatal and often rapidly progressive neurodegenerative diseases. EEG has long been used in the diagnosis of sporadic Creutzfeldt-Jakob disease; however, the characteristic waveforms do not occur in all types of prion diseases. Here, we re-evaluate the utility of EEG by focusing on the development of biomarkers. We test whether abnormal quantitative EEG parameters can be used to measure disease progression in prion diseases or predict disease onset in healthy individuals at risk of disease. Methods In the National Prion Monitoring Cohort study, we did quantitative encephalography on 301 occasions in 29 healthy controls and 67 patients with prion disease. The patients had either inherited prion disease or sporadic Creutzfeldt-Jakob disease. We computed the main background frequency, the α and θ power and the α/θ power ratio, then averaged these within 5 electrode groups. These measurements were then compared among participant groups and correlated with functional and cognitive scores cross-sectionally and longitudinally. Results We found lower main background frequency, α power and α/θ power ratio and higher θ power in patients compared to control participants. The main background frequency, the power in the α band and the α/θ power ratio also differed in a consistent way among the patient groups. Moreover, the main background frequency and the α/θ power ratio correlated significantly with functional and cognitive scores. Longitudinally, change in these parameters also showed significant correlation with the change in clinical and cognitive scores. Conclusions Our findings support the use of quantitative EEG to follow the progression of prion disease, with potential to help evaluate the treatment effects in future clinical-trials. PMID:27413165

  20. Chronic wasting disease and atypical forms of BSE and scrapie are not transmissible to mice expressing wild-type levels of human PrP

    USDA-ARS?s Scientific Manuscript database

    The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has demonstrated that cattle TSEs can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several new TSEs in shee...

  1. Birefringence Measurements of Spherulites formed in β-Lactoglobulin

    NASA Astrophysics Data System (ADS)

    Hardin, Eric; Kirkwood, Brad; Loman, Jazmine; Herat, Athula; Mahmood, Rizwan; Domike, Kristin

    2009-03-01

    Many proteins have a propensity to aggregate into amyloid fibril containing spherulite-like structures. In some instances these spherulitic protein aggregates have been observed in people suffering from a number of neurodegenerative diseases, including Alzheimer's, Parkinson's, and Creutzfeldt-Jakob's. However, the exact role these aggregates play in the body, their internal structure, and the aggregation mechanism still remains a mystery. The model protein used in our study, β-lactoglobulin (BLG), produce spherulites under low pH and high temperature conditions. We report birefringence measurement on BLG using phase retardation method as a function of temperature. Birefringence (˜0.0022 ± 0.0002) data suggest very weak ordering within the spherulites. These spherulites seem to disappear when we added an extensively studied thermotropic liquid crystal [4'-pentyl-4-cyanobiphenyl (5CB)] in β-Lactoglobulin + water+ hydrochloric acid. Our preliminary data suggests that the strong interaction energy between the two systems may lead to the destruction of spherulites.

  2. [Prions: definition and diseases].

    PubMed

    Hernández-Albújar, S; García-Tobaruela, A; Torres Rodríguez, E; Pacheco Cuadros, R; Vázquez Rodríguez, J J

    1999-12-01

    In this article we review the concept and terminology of prions, their replication and some current hypothesis on the nature of these infectious agents causing neurodegenerative diseases. This revision also summarizes the etiopathogenic, epidemiological, clinical and neuropathological features of the prion diseases or human transmissible spongiform encephalopathies, and some methods for their early diagnosis. Finally, we discuss the possible link between the bovine spongiform encephalopathy and the new cases of Creutzfeldt-Jakob disease identified in the United Kingdom.

  3. [From the Scrapie syndrome of sheep and goat to the mad cow disease - the history of the discovery of prion].

    PubMed

    Liu, Rui; Weng, Yi

    2009-05-01

    Since the discovery of Scrapie Syndrome in sheep and goats in 1730, there emerged a series of diseases such as Creutzfeldt-Jakob disease, kuru disease and mad cow disease etc. In the research of kuru disease, the American scientist D. Carlteton Gajdusek found a new virus without the characteristic of DNA and RNA, which was awarded the Nobel Prize in physiology in 1976. Since then another American scientist, Stanley B. Prusiner, found a new virus-prion, taking protein as the genetic medium, which was awarded the Nobel prize in physiology and medicine in 1997. The discovery of prion is a great landmark in the research of life science, which laid a theoretical foundation for people to conquer a series of diseases such as Scrapie syndrome in sheep and goats, Creutzfeldt-Jakob disease, kuru disease and mad cow disease etc.

  4. Disease Burden of 32 Infectious Diseases in the Netherlands, 2007-2011

    PubMed Central

    Bouwknegt, Martijn; Kretzschmar, Mirjam E.; Mangen, Marie-Josée J.; Wallinga, Jacco; de Melker, Hester E.

    2016-01-01

    Background Infectious disease burden estimates provided by a composite health measure give a balanced view of the true impact of a disease on a population, allowing the relative impact of diseases that differ in severity and mortality to be monitored over time. This article presents the first national disease burden estimates for a comprehensive set of 32 infectious diseases in the Netherlands. Methods and Findings The average annual disease burden was computed for the period 2007–2011 for selected infectious diseases in the Netherlands using the disability-adjusted life years (DALY) measure. The pathogen- and incidence-based approach was adopted to quantify the burden due to both morbidity and premature mortality associated with all short and long-term consequences of infection. Natural history models, disease progression probabilities, disability weights, and other parameters were adapted from previous research. Annual incidence was obtained from statutory notification and other surveillance systems, which was corrected for under-ascertainment and under-reporting. The highest average annual disease burden was estimated for invasive pneumococcal disease (9444 DALYs/year; 95% uncertainty interval [UI]: 8911–9961) and influenza (8670 DALYs/year; 95% UI: 8468–8874), which represents 16% and 15% of the total burden of all 32 diseases, respectively. The remaining 30 diseases ranked by number of DALYs/year from high to low were: HIV infection, legionellosis, toxoplasmosis, chlamydia, campylobacteriosis, pertussis, tuberculosis, hepatitis C infection, Q fever, norovirus infection, salmonellosis, gonorrhoea, invasive meningococcal disease, hepatitis B infection, invasive Haemophilus influenzae infection, shigellosis, listeriosis, giardiasis, hepatitis A infection, infection with STEC O157, measles, cryptosporidiosis, syphilis, rabies, variant Creutzfeldt-Jakob disease, tetanus, mumps, rubella, diphtheria, and poliomyelitis. The very low burden for the latter five

  5. Disease Burden of 32 Infectious Diseases in the Netherlands, 2007-2011.

    PubMed

    van Lier, Alies; McDonald, Scott A; Bouwknegt, Martijn; Kretzschmar, Mirjam E; Havelaar, Arie H; Mangen, Marie-Josée J; Wallinga, Jacco; de Melker, Hester E

    2016-01-01

    Infectious disease burden estimates provided by a composite health measure give a balanced view of the true impact of a disease on a population, allowing the relative impact of diseases that differ in severity and mortality to be monitored over time. This article presents the first national disease burden estimates for a comprehensive set of 32 infectious diseases in the Netherlands. The average annual disease burden was computed for the period 2007-2011 for selected infectious diseases in the Netherlands using the disability-adjusted life years (DALY) measure. The pathogen- and incidence-based approach was adopted to quantify the burden due to both morbidity and premature mortality associated with all short and long-term consequences of infection. Natural history models, disease progression probabilities, disability weights, and other parameters were adapted from previous research. Annual incidence was obtained from statutory notification and other surveillance systems, which was corrected for under-ascertainment and under-reporting. The highest average annual disease burden was estimated for invasive pneumococcal disease (9444 DALYs/year; 95% uncertainty interval [UI]: 8911-9961) and influenza (8670 DALYs/year; 95% UI: 8468-8874), which represents 16% and 15% of the total burden of all 32 diseases, respectively. The remaining 30 diseases ranked by number of DALYs/year from high to low were: HIV infection, legionellosis, toxoplasmosis, chlamydia, campylobacteriosis, pertussis, tuberculosis, hepatitis C infection, Q fever, norovirus infection, salmonellosis, gonorrhoea, invasive meningococcal disease, hepatitis B infection, invasive Haemophilus influenzae infection, shigellosis, listeriosis, giardiasis, hepatitis A infection, infection with STEC O157, measles, cryptosporidiosis, syphilis, rabies, variant Creutzfeldt-Jakob disease, tetanus, mumps, rubella, diphtheria, and poliomyelitis. The very low burden for the latter five diseases can be attributed to the

  6. Development of Aptamer Beacons for Antemortem Diagnosis of Chronic Wasting Disease

    DTIC Science & Technology

    2006-05-01

    encephalopathies (TSE) such as mad cow disease and its human equivalent variant Creutzfeldt-Jakob disease are transmitted by ingestion of meat ...too may be transmissible to human beings via ingestion of contaminated meat . Reliable antemortem diagnostic tests for TSEs are necessary for control...Purified recombinant bovine PrPc Negative selection of aptamer to PrPc Removes aptamers from pools which also recognize PrPc Same as proposed, but

  7. Prion diseases.

    PubMed

    McKintosh, Edward; Tabrizi, Sarah J; Collinge, John

    2003-04-01

    Prion diseases are incurable neurodegenerative conditions affecting both animals and humans. They may be sporadic, infectious, or inherited in origin. Human prion diseases include Creutzfeldt-Jakob desease (CJD), Gerstmann-Straussler-Scheinker disease, kuru, and fatal familial insomnia. The appearance of variant CJD, and the demonstration that is caused by strains indistinguishable from bovine spongiform encephalopathy (BSE) in cattle, has led to the threat of a major epidemic of human prion disease in the UK and other countries where widespread dietary exposure to bovine prions has occurred. This article reviews the history and epidemiology of these diseases, and then focuses on important areas of current research in human prion disorders.

  8. Clinical findings of a probable case of MM2-cortical-type sporadic Creutzfeldt-Jakob disease with antibodies to anti-N-terminus of α-enolase.

    PubMed

    Hayashi, Yuichi; Yamada, Megumi; Kimura, Akio; Asano, Takahiko; Satoh, Katsuya; Kitamoto, Tetsuyuki; Yoneda, Maokoto; Inuzuka, Takashi

    2017-10-02

    We report the case of a 76-year-old woman presenting with 47-month history of progressive dementia and cortical blindness with no family history. Antibodies against thyroid glands and the N-terminus of α-enolase (NAE) were detected in her serum. Neurological examination revealed progressive dementia, frontal signs, visual disturbance, and exaggerated bilateral tendon reflexes in both legs. Diffusion MRI showed cortical hyper-intensities in the bilateral occipital and parietal, and the left frontal and temporal cortices. (99m)Tc-ethyl cysteinate dimer-single photon emission computed tomography indicated decreased regional cerebral blood flow throughout the bilateral parietal lobes and partially in the left frontal and temporal lobes. PRNP gene analysis showed no mutations with methionine homozygosity at codon 129 in peripheral blood. Cerebrospinal fluid examination, including 14-3-3 and total tau protein detection, revealed normal levels; however, prion proteins were amplified by the real-time quaking-induced conversion method. Hashimoto's encephalopathy was excluded on the basis of unresponsiveness to corticosteroids. The symptoms progressed slowly. Periodic sharp-wave complexes were observed on electroencephalogram 36 months after the onset of symptoms; the patient reached a state of akinetic mutism at 47 months. This was a probable case of MM2-cortical-type sCJD with anti-NAE antibodies based on the World Health Organization (WHO) diagnostic criteria for sCJD, genetic information, and the slowly progressive course. However, this case did not meet with the probable WHO diagnostic criteria until 3 years after symptom onset, highlighting the difficulty of diagnosing a living case of the MM2-type of sCJD. Therefore, establishment of clinical diagnostic criteria for MM2-type of sCJD is required.

  9. Human growth hormone-related latrogenic Creutzfeldt-Jakob disease: Search for a genetic susceptibility by analysis of the PRNP coding region

    SciTech Connect

    Jaegly, A.; Boussin, F.; Deslys, J.P.

    1995-05-20

    The human PRNP gene encoding PrP is located on chromosome 20 and consists of two exons and a single intron. The open reading frame is entirely fitted into the second exon. Genetic studies indicate that all of the familial and several sporadic forms of TSSEs are associated with mutations in the PRNP 759-bp coding region. Moreover, homozygosity at codon 129, a locus harboring a polymorphism among the general population, was proposed as a genetic susceptibility marker for both sporadic and iatrogenic CJD. To assess whether additional genetic predisposition markers exist in the PRNP gene, the authors sequenced the PRNP coding region of 17 of the 32 French patients who developed a hGH-related CJD.

  10. Brain-water diffusion coefficients reflect the severity of inherited prion disease

    PubMed Central

    Hyare, H.; Wroe, S.; Siddique, D.; Webb, T.; Fox, N. C.; Stevens, J.; Collinge, J.; Yousry, T.; Thornton, J. S.

    2010-01-01

    = Brief Psychiatric Rating Scale; BSE = bovine spongiform encephalopathy; CDR = Clinician's Dementia Rating Scale; CGIS = Clinician's Global Impression of Disease; CI = confidence interval; DWI = diffusion-weighted imaging; FLAIR = fluid-attenuated inversion recovery; FOV = field of view; GM = gray matter; LC = left head of caudate; LP = left putamen; LPu = left pulvinar; MMSE = Mini-Mental State Examination; NBV = normalized brain volume; PH = peak height; PL = peak location; RC = right head of caudate; RP = right putamen; RPu = right pulvinar; ROI = region of interest; sCJD = sporadic Creutzfeldt-Jakob disease; TE = echo time; TI = inversion time; TR = repetition time; vCJD = variant Creutzfeldt-Jakob disease; WB = whole brain; WM = white matter. PMID:20177119

  11. Dental practice implications of prion diseases.

    PubMed

    Bebermeyer, Richard D; Powell, Jonathan F; Hobdell, Martin H; Durban, Elisa M

    2003-01-01

    This review article discusses dental practice implications of prion diseases, including Creutzfeldt-Jakob disease. The current universal precautions used for infection control in dentistry do not inactivate infectious prions. There is a theoretical, yet real risk of prion disease transmission through dental treatment, although the magnitude of that risk has not yet been determined. Medical, family, and travel histories can demonstrate the need for implementing improved levels of infection control. Best practices include the following: For certain cases, single-use disposable dental instruments should be used. Those instruments that are not disposable, should have a thorough physical cleaning, be soaked in hot 1N sodium hydroxide solution for 1 hour, and then autoclaved in a vacuum or porous-load autoclave at 134 degrees C to 138 degrees C for 18 to 20 minutes. Dental and other health care professionals need to understand prion diseases, and for best practice, consider implementing recommended changes to infection-control measures, since current practices do not destroy infectious prions.

  12. Prion disease tempo determined by host-dependent substrate reduction

    PubMed Central

    Mays, Charles E.; Kim, Chae; Haldiman, Tracy; van der Merwe, Jacques; Lau, Agnes; Yang, Jing; Grams, Jennifer; Di Bari, Michele A.; Nonno, Romolo; Telling, Glenn C.; Kong, Qingzhong; Langeveld, Jan; McKenzie, Debbie; Westaway, David; Safar, Jiri G.

    2014-01-01

    The symptoms of prion infection can take years or decades to manifest following the initial exposure. Molecular markers of prion disease include accumulation of the misfolded prion protein (PrPSc), which is derived from its cellular precursor (PrPC), as well as downregulation of the PrP-like Shadoo (Sho) glycoprotein. Given the overlapping cellular environments for PrPC and Sho, we inferred that PrPC levels might also be altered as part of a host response during prion infection. Using rodent models, we found that, in addition to changes in PrPC glycosylation and proteolytic processing, net reductions in PrPC occur in a wide range of prion diseases, including sheep scrapie, human Creutzfeldt-Jakob disease, and cervid chronic wasting disease. The reduction in PrPC results in decreased prion replication, as measured by the protein misfolding cyclic amplification technique for generating PrPSc in vitro. While PrPC downregulation is not discernible in animals with unusually short incubation periods and high PrPC expression, slowly evolving prion infections exhibit downregulation of the PrPC substrate required for new PrPSc synthesis and as a receptor for pathogenic signaling. Our data reveal PrPC downregulation as a previously unappreciated element of disease pathogenesis that defines the extensive, presymptomatic period for many prion strains. PMID:24430187

  13. The Structure of Intrinsically Disordered Peptides Implicated in Amyloid Diseases: Insights from Fully Atomistic Simulations

    NASA Astrophysics Data System (ADS)

    Wu, Chun; Shea, Joan-Emma

    Protein aggregation involves the self-assembly of proteins into large β-sheet-rich complexes. This process can be the result of aberrant protein folding and lead to "amyloidosis," a condition characterized by deposits of protein aggregates known as amyloids on various organs of the body [1]. Amyloid-related diseases include, among others, Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and type II diabetes [2, 3, 4]. In other instances, however, protein aggregation is not a pathological process, but rather a functional one, with aggregates serving as structural scaffolds in a number of organisms [5].

  14. Manufacture of plasma-derived products in France and measures to prevent the risk of vCJD transmission: precautionary measures and efficacy of manufacturing processes in prion removal.

    PubMed

    Flan, Benoît; Arrabal, Samuel

    2007-05-01

    The emergence of the variant Creutzfeldt-Jakob disease in the mid 1990s soon raised concerns about its possible transmission through the use of blood and plasma-derived medicinal products. A risk analysis approach was initiated by health authorities, based on updated scientific knowledge and precautionary measures were implemented in France and other countries for the management of this new possible risk. Assessment of the vCJD risk is based on epidemiology and estimates of the number of potential cases in the future, on blood infectivity data from models of transmissible spongiform encephalopathies and on data from studies of the capacity of manufacturing processes to remove the agent, should it be present in the plasma of infected donors. The transmission of vCJD by non leukocyte-depleted labile blood components has recently been confirmed. There have been no reports of cases associated with the use of plasma-derived products and the scientific data, and risk analyses for those plasma products, which are of the greatest therapeutic interest, support their safety with respect to this transmission risk. The precautionary measures applied in France and the data contributing to the risk assessment of plasma products are reviewed and updated in the present paper. The uncertainties, which remain, are also addressed and discussed, as well as the ongoing research and developments in this area.

  15. A novel form of human disease with a protease-sensitive prion protein and heterozygosity methionine/valine at codon 129: Case report.

    PubMed

    Rodríguez-Martínez, Ana B; Garrido, Joseba M; Zarranz, Juan J; Arteagoitia, Jose M; de Pancorbo, Marian M; Atarés, Begoña; Bilbao, Miren J; Ferrer, Isidro; Juste, Ramón A

    2010-10-25

    Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder in humans included in the group of Transmissible Spongiform Encephalopathies or prion diseases. The vast majority of sCJD cases are molecularly classified according to the abnormal prion protein (PrPSc) conformations along with polymorphism of codon 129 of the PRNP gene. Recently, a novel human disease, termed "protease-sensitive prionopathy", has been described. This disease shows a distinct clinical and neuropathological phenotype and it is associated to an abnormal prion protein more sensitive to protease digestion. We report the case of a 75-year-old-man who developed a clinical course and presented pathologic lesions compatible with sporadic Creutzfeldt-Jakob disease, and biochemical findings reminiscent of "protease-sensitive prionopathy". Neuropathological examinations revealed spongiform change mainly affecting the cerebral cortex, putamen/globus pallidus and thalamus, accompanied by mild astrocytosis and microgliosis, with slight involvement of the cerebellum. Confluent vacuoles were absent. Diffuse synaptic PrP deposits in these regions were largely removed following proteinase treatment. PrP deposition, as revealed with 3F4 and 1E4 antibodies, was markedly sensitive to pre-treatment with proteinase K. Molecular analysis of PrPSc showed an abnormal prion protein more sensitive to proteinase K digestion, with a five-band pattern of 28, 24, 21, 19, and 16 kDa, and three aglycosylated isoforms of 19, 16 and 6 kDa. This PrPSc was estimated to be 80% susceptible to digestion while the pathogenic prion protein associated with classical forms of sporadic Creutzfeldt-Jakob disease were only 2% (type VV2) and 23% (type MM1) susceptible. No mutations in the PRNP gene were found and genotype for codon 129 was heterozygous methionine/valine. A novel form of human disease with abnormal prion protein sensitive to protease and MV at codon 129 was described. Although clinical signs were

  16. A novel form of human disease with a protease-sensitive prion protein and heterozygosity methionine/valine at codon 129: Case report

    PubMed Central

    2010-01-01

    Background Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder in humans included in the group of Transmissible Spongiform Encephalopathies or prion diseases. The vast majority of sCJD cases are molecularly classified according to the abnormal prion protein (PrPSc) conformations along with polymorphism of codon 129 of the PRNP gene. Recently, a novel human disease, termed "protease-sensitive prionopathy", has been described. This disease shows a distinct clinical and neuropathological phenotype and it is associated to an abnormal prion protein more sensitive to protease digestion. Case presentation We report the case of a 75-year-old-man who developed a clinical course and presented pathologic lesions compatible with sporadic Creutzfeldt-Jakob disease, and biochemical findings reminiscent of "protease-sensitive prionopathy". Neuropathological examinations revealed spongiform change mainly affecting the cerebral cortex, putamen/globus pallidus and thalamus, accompanied by mild astrocytosis and microgliosis, with slight involvement of the cerebellum. Confluent vacuoles were absent. Diffuse synaptic PrP deposits in these regions were largely removed following proteinase treatment. PrP deposition, as revealed with 3F4 and 1E4 antibodies, was markedly sensitive to pre-treatment with proteinase K. Molecular analysis of PrPSc showed an abnormal prion protein more sensitive to proteinase K digestion, with a five-band pattern of 28, 24, 21, 19, and 16 kDa, and three aglycosylated isoforms of 19, 16 and 6 kDa. This PrPSc was estimated to be 80% susceptible to digestion while the pathogenic prion protein associated with classical forms of sporadic Creutzfeldt-Jakob disease were only 2% (type VV2) and 23% (type MM1) susceptible. No mutations in the PRNP gene were found and genotype for codon 129 was heterozygous methionine/valine. Conclusions A novel form of human disease with abnormal prion protein sensitive to protease and MV at codon 129 was

  17. Prion disease: possible implications for oral health care.

    PubMed

    Porter, Stephen R

    2003-11-01

    Prion diseases are a group of rare fatal neurodegenerative disorders in humans and animals that are histopathologically characterized by spongiform change within the central nervous system. The author reviewed all available case reports and any studies of the oral aspects of prion diseases published in peer-reviewed journals and available via PubMed. He then outlined the risk of nosocomial transmission of prions in dental health care. Sporadic Creutzfeldt-Jakob disease, or sCJD, is the most common of the acquired human prion disorders, and it typically affects elderly people and leads to rapid death. In contrast, variant CJD, or vCJD, has affected young adults from Europe, giving rise to a slow onset disorder comprising both psychiatric and neurological upset. Oral neurological manifestations are rare and seem to occur only in people with vCJD; there are no oral mucosal or gingival manifestations of prion disease. Prions can be detected in the oral tissues--usually the gingivae and dental pulp--of animals experimentally infected with prions. In contrast, prions have not been detected in the pulpal tissue of people with sCJD, and there are no data of pulpal infection in vCJD. There also are no data suggesting that prions are transmitted easily in the dental setting, but there remains the rare risk of such transmission if appropriate infection control measures are not adhered to. Few people in the United States and worldwide have prion disease. Oral manifestations are rare. Evidence suggests that the risk of transmission and acquisition of a prion infection as a result of dental treatment is rare, if appropriate infection control measures are maintained.

  18. R47H TREM2 variant increases risk of typical early-onset Alzheimer’s disease but not of prion or frontotemporal dementia

    PubMed Central

    CF, Slattery; J, Beck; L, Harper; G, Adamson; Z, Abdi; J, Uphill; T, Campbell; R, Druyeh; CJ, Mahoney; JD, Rohrer; J, Kenny; J, Lowe; KK, Leung; J, Barnes; SL, Clegg; M, Blair; JM, Nicholas; RJ, Guerreiro; JB, Rowe; C, Ponto; I, Zerr; H, Kretzschmar; P, Gambetti; SJ, Crutch; JD, Warren; MN, Rossor; NC, Fox; J, Collinge; JM, Schott; S, Mead

    2015-01-01

    Background Rare TREM2 variants are significant risk factors for Alzheimer’s disease. Methods We used next generation sequencing of the whole gene (n=700), exon 2 Sanger sequencing (n=2634), p.R47H genotyping (n=3518) and genome wide association study imputation (n=13048) to determine whether TREM2 variants are risk factors or phenotypic modifiers in patients with Alzheimer’s disease (n=1002), frontotemporal dementia (n=358), sporadic (n=2500) and variant (n=115) Creutzfeldt-Jakob disease. Results We confirm only p.R47H as a risk factor for Alzheimer’s disease (OR=2.19; 95%CI=1.04-4.51; P=0.03). p.R47H does not significantly alter risk for frontotemporal dementia (OR=0.81), variant or sporadic Creutzfeldt-Jakob disease (OR=1.06 95%CI=0.66-1.69) in our cohorts. Individuals with p.R47H associated Alzheimer’s (n=12) had significantly earlier symptom onset than individuals with no TREM2 variants (n=551) (55.2years vs. 61.7years, P=0.02). We note that heterozygous p.R47H Alzheimer’s disease is memory led and otherwise indistinguishable from “typical” sporadic Alzheimer’s. Conclusion We find p.R47H is a risk factor for Alzheimer’s disease, but not frontotemporal dementia or prion disease. PMID:25160042

  19. Transmission of scrapie prions to primate after an extended silent incubation period

    USDA-ARS?s Scientific Manuscript database

    Classical bovine spongiform encephalopathy (c-BSE) is an animal prion disease that also causes variant Creutzfeldt-Jakob disease in humans. Over the past decades, c-BSE's zoonotic potential has been the driving force in establishing extensive protective measures for animal and human health. In compl...

  20. Autopsy case of Creutzfeldt-Jakob disease with Met/Val heterozygosity at codon 129 and type 1 protease-resistant prion protein presenting some florid-type plaques and many Kuru plaques in the cerebellum.

    PubMed

    Kawauchi, Yoko; Kamitani, Toshiaki; Yagishita, Saburo; Kitamoto, Tetsuyuki; Kishida, Hitaru

    2006-08-01

    We report an atypical case of CJD. The clinical course was similar to a classic CJD phenotype, but histopathological study revealed several florid-type plaques in the amygdale and abundant Kuru plaques in the cerebellum that are atypical of classic CJD. Molecular analysis showed methionine/valine heterozygosity at codon 129 and no pathogenic mutation in the coding region of the prion protein gene. Western immunoblots revealed type 1 protease-resistant prion protein (PrPres), and a ration analysis of PrPres showed a high ratio of the diglycosylated form and a low ratio of the non-glycosylated form. Our case could not be precisely classified in any of Parchi's six variants. It suggests the existence of some factors that determine the phenotypic variability other than the codon 129 genotypes in the PrP gene or the physicochemical properties of PrPres.

  1. Neuroimaging Biomarkers of Neurodegenerative Diseases and Dementia

    PubMed Central

    Risacher, Shannon L.; Saykin, Andrew J.

    2014-01-01

    Neurodegenerative disorders leading to dementia are common diseases that affect many older and some young adults. Neuroimaging methods are important tools for assessing and monitoring pathological brain changes associated with progressive neurodegenerative conditions. In this review, the authors describe key findings from neuroimaging studies (magnetic resonance imaging and radionucleotide imaging) in neurodegenerative disorders, including Alzheimer’s disease (AD) and prodromal stages, familial and atypical AD syndromes, frontotemporal dementia, amyotrophic lateral sclerosis with and without dementia, Parkinson’s disease with and without dementia, dementia with Lewy bodies, Huntington’s disease, multiple sclerosis, HIV-associated neurocognitive disorder, and prion protein associated diseases (i.e., Creutzfeldt-Jakob disease). The authors focus on neuroimaging findings of in vivo pathology in these disorders, as well as the potential for neuroimaging to provide useful information for differential diagnosis of neurodegenerative disorders. PMID:24234359

  2. ['Variant of Creutzfeldt-Jacob disease and blood transfusion'; report of the Dutch Health Council].

    PubMed

    van Aken, W G

    2001-07-28

    The new variant form of Creutzfeldt-Jakob Disease (vCJD), which has been diagnosed in about 100 patients--mostly in the United Kingdom (UK)--is considered to be associated with the consumption of beef contaminated with the agent bovine spongi-form encephalopathy (BSE). Although no cases of vCJD have been reported until now in the Netherlands, large quantities of beef have been imported from the UK in previous years; furthermore about 17 cattle with BSE have been detected in the Netherlands. Concern about the possible transmission of vCJD via blood and blood-products has led to a number of countries taking precautionary measures. Following questions raised by the Minister of Health, Welfare and Sport, the Health Council of the Netherlands issued a report to address the need for certain precautionary measures such as the leukodepletion of blood and the exclusion of donors at risk for vCJD. The Health Council recommends the routine leukodepletion of cellular blood components. The exclusion of donors who have resided in the UK for six or more months during the period 1980-1996, was considered to be insufficient to contribute to risk reduction. The Minister has recently decided to follow these two recommendations. However, she is of the opinion that the Health Council's recommendation to exclude all donors who have previously been transfused with cellular blood components is unnecessary. A common European position regarding such precautionary measures is deemed to be necessary. This would allow the exchange of blood components between countries and would also prevent donors, patients and the public at large from being confused or uncertain about the safety of blood components.

  3. Prion Disease Induces Alzheimer Disease-Like Neuropathologic Changes.

    PubMed

    Tousseyn, Thomas; Bajsarowicz, Krystyna; Sánchez, Henry; Gheyara, Ania; Oehler, Abby; Geschwind, Michael; DeArmond, Bernadette; DeArmond, Stephen J

    2015-09-01

    We examined the brains of 266 patients with prion disease (PrionD) and found that 46 patients (17%) had Alzheimer disease (AD)-like changes. To explore potential mechanistic links between PrionD and AD, we exposed human brain aggregates (BrnAggs) to a brain homogenate from a patient with sporadic Creutzfeldt-Jakob disease and found that neurons in human BrnAggs produced many β-amyloid (Aβ; Aβ42) inclusions, whereas uninfected control-exposed human BrnAggs did not. Western blot analysis of 20 pooled Creutzfeldt-Jakob disease-infected BrnAggs verified Aβ42 levels higher than those in controls. We next examined the CA1 region of the hippocampus from 14 patients with PrionD and found that 5 patients had low levels of scrapie-associated prion protein (PrP), many Aβ42 intraneuronal inclusions, low apolipoprotein E-4 (APOE-4), and no significant nerve cell loss. Seven patients had high levels of PrP, low Aβ42, high APOE-4, and 40% nerve cell loss, suggesting that APOE-4 and PrP together cause neuron loss in PrionD. There were also increased levels of hyperphosphorylated tau protein (Hτ) and Hτ-positive neuropil threads and neuron bodies in both PrionD and AD groups. The brains of 6 age-matched control patients without dementia did not contain Aβ42 deposits; however, there were rare Hτ-positive threads in 5 controls, and 2 controls had few Hτ-positive nerve cell bodies. We conclude that PrionD may trigger biochemical changes similar to those triggered by AD and suggest that PrionD is a disease involving PrP, Aβ42, APOE-4, and abnormal tau.

  4. Investigating the association of ApoE genotypes with blood-brain barrier dysfunction measured by cerebrospinal fluid-serum albumin ratio in a cohort of patients with different types of dementia.

    PubMed

    Karch, André; Manthey, Henrike; Ponto, Claudia; Hermann, Peter; Heinemann, Uta; Schmidt, Christian; Zerr, Inga

    2013-01-01

    Since more than a decade ApoE is known to be a strong risk factor for Alzheimer's disease (AD); however, molecular pathways mediating this risk are still unclear. In recent years it has been hypothesized that ApoE might play a role in the disintegration of blood-brain barrier (BBB). In the present study we addressed the question if ApoE genotypes might be associated with BBB function measured by albumin ratio (QAlb) in a large cohort of patients with different types of dementia. Five hundred twenty (520) patients with Creutzfeldt-Jakob disease (CJD, n = 350), Alzheimer's disease (n = 71) and cerebral small vessel disease (n = 99) were assessed for their ApoE genotype. BBB function was measured in all patients using QAlb and was compared between ApoE genotypes. Dominant and additive genetic models were assumed in order to investigate the potential effect of ApoE on BBB function. We observed no systematic differences in QAlb between ApoE genotypes within the present study. Increased QAlb levels were shown for those without E3 allele in the subgroup of CJD patients when assuming a dominant genetic model (p = 0.035). This could not be confirmed for patients with other forms of dementia (p = 0.234). Although there was some evidence for a protective effect of E3 alleles in CJD patients, this study does not support the hypothesis of a systematic role of ApoE genotypes in BBB function in individuals with a diagnosis of dementia. Thus, changes in BBB function do not seem to contribute to the increased risk of cognitive decline associated with certain ApoE genotypes. The interpretation of the results of this study must take into account that BBB function was only assessed by measuring QAlb which has been shown to be a good marker for overall BBB integrity but might not reflect all qualities of the barrier.

  5. [Doctor Francoise Cathala and history of prions diseases].

    PubMed

    Court, L; Hauw, J-J

    2015-12-01

    Doctor Françoise Cathala Pagesy, MD, MS, born on July 7, 1921 in Paris, passed away peacefully at home on November 5, 2012. Unconventional, passionate and enthusiastic neurologist and virologist, she devoted her life to research on latent and slow viral infections, specializing mainly on unconventional transmissible agents or prions. As a research member of Inserm (French Institute for Medical Research), she soon joined the team of Carlton Gajdusek (the NINCDS - National Institute of Nervous Central System and Stroke - of NIH), who first demonstrated the transmissibility of kuru and Creutzfeldt-Jakob disease to monkeys. When she came back to Paris, where she was followed by one of NIH members, Paul Brown, she joined the Centre de Recherches du Service de Santé des Armées (Army Health Research Center), in Percy-Clamart, where she found the experimental design and the attentive help needed for her research, which appeared heretical to many French virologists, including some authorities. A large number of research programs were set up with numerous collaborations involving CEA (Center for Atomic Energy) and other institutions in Paris and Marseilles on epidemiology, results of tissue inoculation, electrophysiology and neuropathology of human and animal prions diseases, and resistance of the infectious agent. International symposia were set up, where met, in the Val-de-Grâce hospital in Paris, the research community on "slow viral diseases". Stanley Prusiner introduced the concept - then badly accepted and still in evolution - of prion, a protein only infectious agent. Before retiring from Inserm, Françoise Cathala predicted and was involved in some of the huge sanitary crises in France. These were, first, Creutzfeldt-Jakob disease from contaminated growth hormone extracted from cadavers, which led parents to instigate legal procedure - a quite unusual practice in France. The second was Mad cow disease in the United Kingdom then in France, followed by new variant

  6. Selective Neuronal Vulnerability in Human Prion Diseases

    PubMed Central

    Guentchev, Marin; Wanschitz, Julia; Voigtländer, Till; Flicker, Helga; Budka, Herbert

    1999-01-01

    Human transmissible spongiform encephalopathies (TSEs) or prion diseases are neurodegenerative disorders of infectious, inherited or sporadic origin and include Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), kuru and fatal familial insomnia (FFI). Clinicopathologic features of FFI differ markedly from other human TSEs. Previous studies demonstrated selective neuronal vulnerability of parvalbumin positive (PV+) GABAergic inhibitory interneurons in sporadic CJD and experimental TSEs. In this report we show uniform severe loss of PV+ neurons also in other TSEs such as GSS, kuru, new variant and familial CJD. In contrast, these neurons are mostly well preserved, or only moderately reduced, in FFI. Only PV+ neurons surrounded by isolectin-B4 positive perineuronal nets were severely affected in TSEs, suggesting a factor residing in this type of extracellular matrix around PV+ neurons as modulator for the selective neuronal vulnerability. PMID:10550300

  7. Endpoint Quaking-Induced Conversion: a Sensitive, Specific, and High-Throughput Method for Antemortem Diagnosis of Creutzfeldt-Jacob Disease

    PubMed Central

    Vendramelli, Robert; Sloan, Angela; Waitt, Brooks; Podhorodecki, Lisa; Godal, Debra

    2016-01-01

    The Prion Laboratory Section of the Public Health Agency of Canada supports heath care professionals dealing with patients suspected to have Creutzfeldt-Jakob disease (CJD) by testing cerebrospinal fluid (CSF) for protein markers of CJD. To better serve Canadian diagnostic requirements, a quaking-induced conversion (QuIC)-based assay has been added to the test panel. The QuIC tests exploit the ability of disease-associated prion protein, found in the CSF of a majority of CJD patients, to convert a recombinant prion protein (rPrP) into detectable amounts of a misfolded, aggregated form of rPrP. The rPrP aggregates interact with a specific dye, causing a measurable change in the dye's fluorescence emission spectrum. Optimal test and analysis parameters were empirically determined. Taking both practical and performance considerations into account, an endpoint QuIC (EP-QuIC) configuration was chosen. EP-QuIC uses a thermo-mixer to perform the shaking necessary to produce the quaking-induced conversions. Fluorescence readings are obtained from a microwell fluorescence reader only at the beginning and the end of EP-QuIC reactions. Samples for which the relative fluorescence unit ratio between the initial and final readings represent a ≥4 increase in signal intensity in at least two of the three replicates are classified as positive. A retrospective analysis of 91 CSF samples that included 45 confirmed cases of CJD and 46 non-CJD cases was used to estimate the performance characteristics of the EP-QuIC assay. The diagnostic sensitivity and specificity of the EP-QuIC test of this set of samples were 98 and 91%, respectively. PMID:27076662

  8. Copper and the Prion Protein: Methods, Structures, Function, and Disease

    NASA Astrophysics Data System (ADS)

    Millhauser, Glenn L.

    2007-05-01

    The transmissible spongiform encephalopathies (TSEs) arise from conversion of the membrane-bound prion protein from PrPC to PrPSc. Examples of the TSEs include mad cow disease, chronic wasting disease in deer and elk, scrapie in goats and sheep, and kuru and Creutzfeldt-Jakob disease in humans. Although the precise function of PrPC in healthy tissues is not known, recent research demonstrates that it binds Cu(II) in an unusual and highly conserved region of the protein termed the octarepeat domain. This review describes recent connections between copper and PrPC, with an emphasis on the electron paramagnetic resonance elucidation of the specific copper-binding sites, insights into PrPC function, and emerging connections between copper and prion disease.

  9. Prospects for safe and effective vaccines against prion diseases.

    PubMed

    Mabbott, Neil Andrew

    2015-01-01

    Prion diseases are subacute neurodegenerative diseases that affect humans and animals. An abnormally folded isoform (PrP(Sc)) of the host cellular prion protein is considered to constitute the major, if not sole, component of the infectious prion. The occurrence of variant Creutzfeldt-Jakob disease in humans most likely arose due to consumption of food contaminated with bovine spongiform encephalopathy prions. The demonstration that some prion infections may have the capacity to transmit to other species, especially humans, has focused attention on the development of safe and effective vaccines against these invariably fatal and currently incurable diseases. Although much effort has been invested in the development of safe and effective anti-PrP vaccines, many important issues remain to be resolved.

  10. Rare structural genetic variation in human prion diseases.

    PubMed

    Lukic, Ana; Uphill, James; Brown, Craig A; Beck, John; Poulter, Mark; Campbell, Tracy; Adamson, Gary; Hummerich, Holger; Whitfield, Jerome; Ponto, Claudia; Zerr, Inga; Lloyd, Sarah E; Collinge, John; Mead, Simon

    2015-05-01

    Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfolding of prion protein. Aside from the strong genetic risk conferred by multiple variants of the prion protein gene (PRNP), several other variants have been suggested to confer risk in the most common type, sporadic Creutzfeldt-Jakob disease (sCJD) or in the acquired prion diseases. Large and rare copy number variants (CNVs) are known to confer risk in several related disorders including Alzheimer's disease (at APP), schizophrenia, epilepsy, mental retardation, and autism. Here, we report the first genome-wide analysis for CNV-associated risk using data derived from a recent international collaborative association study in sCJD (n = 1147 after quality control) and publicly available controls (n = 5427). We also investigated UK patients with variant Creutzfeldt-Jakob disease (n = 114) and elderly women from the Eastern Highlands of Papua New Guinea who proved highly resistant to the epidemic prion disease kuru, who were compared with healthy young Fore population controls (n = 395). There were no statistically significant alterations in the burden of CNVs >100, >500, or >1000 kb, duplications, or deletions in any disease group or geographic region. After correction for multiple testing, no statistically significant associations were found. A UK blood service control sample showed a duplication CNV that overlapped PRNP, but these were not found in prion disease. Heterozygous deletions of a 3' region of the PARK2 gene were found in 3 sCJD patients and no controls (p = 0.001, uncorrected). A cell-based prion infection assay did not provide supportive evidence for a role for PARK2 in prion disease susceptibility. These data are consistent with a modest impact of CNVs on risk of late-onset neurologic conditions and suggest that, unlike APP, PRNP duplication is not a causal high-risk mutation.

  11. Chronic wasting disease and atypical forms of bovine spongiform encephalopathy and scrapie are not transmissible to mice expressing wild-type levels of human prion protein.

    PubMed

    Wilson, Rona; Plinston, Chris; Hunter, Nora; Casalone, Cristina; Corona, Cristiano; Tagliavini, Fabrizio; Suardi, Silvia; Ruggerone, Margherita; Moda, Fabio; Graziano, Silvia; Sbriccoli, Marco; Cardone, Franco; Pocchiari, Maurizio; Ingrosso, Loredana; Baron, Thierry; Richt, Juergen; Andreoletti, Olivier; Simmons, Marion; Lockey, Richard; Manson, Jean C; Barron, Rona M

    2012-07-01

    The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several novel TSEs in sheep, cattle and deer have been described and the risk posed to humans by these agents is currently unknown. In this study, we inoculated two forms of atypical BSE (BASE and H-type BSE), a chronic wasting disease (CWD) isolate and seven isolates of atypical scrapie into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP). Upon challenge with these ruminant TSEs, gene-targeted Tg mice expressing human PrP did not show any signs of disease pathology. These data strongly suggest the presence of a substantial transmission barrier between these recently identified ruminant TSEs and humans.

  12. Central and peripheral pathology of kuru: pathological analysis of a recent case and comparison with other forms of human prion disease.

    PubMed

    Brandner, Sebastian; Whitfield, Jerome; Boone, Ken; Puwa, Anderson; O'Malley, Catherine; Linehan, Jacqueline M; Joiner, Susan; Scaravilli, Francesco; Calder, Ian; P Alpers, Michael; Wadsworth, Jonathan D F; Collinge, John

    2008-11-27

    While the neuropathology of kuru is well defined, there are few data concerning the distribution of disease-related prion protein in peripheral tissues. Here we report the investigation of brain and peripheral tissues from a kuru patient who died in 2003. Neuropathological findings were compared with those seen in classical (sporadic and iatrogenic) Creutzfeldt-Jakob disease (CJD) and variant CJD (vCJD). The neuropathological findings of the kuru patient showed all the stereotypical changes that define kuru, with the occurrence of prominent PrP plaques throughout the brain. Lymphoreticular tissue showed no evidence of prion colonization, suggesting that the peripheral pathogenesis of kuru is similar to that seen in classical CJD rather than vCJD. These findings now strongly suggest that the characteristic peripheral pathogenesis of vCJD is determined by prion strain type alone rather than route of infection.

  13. Prionic diseases.

    PubMed

    Araújo, Abelardo Q-C

    2013-09-01

    Prion diseases are neurodegenerative illnesses due to the accumulation of small infectious pathogens containing protein but apparently lacking nucleic acid, which have long incubation periods and progress inexorably once clinical symptoms appear. Prions are uniquely resistant to a number of normal decontaminating procedures. The prionopathies [Kuru, Creutzfeldt-Jakob disease (CJD) and its variants, Gerstmann-Sträussler-Scheinker (GSS) syndrome and fatal familial insomnia (FFI)] result from accumulation of abnormal isoforms of the prion protein in the brains of normal animals on both neuronal and non-neuronal cells. The accumulation of this protein or fragments of it in neurons leads to apoptosis and cell death. There is a strong link between mutations in the gene encoding the normal prion protein in humans (PRNP) - located on the short arm of chromosome 20 - and forms of prion disease with a familial predisposition (familial CJD, GSS, FFI). Clinically a prionopathy should be suspected in any case of a fast progressing dementia with ataxia, myoclonus, or in individuals with pathological insomnia associated with dysautonomia. Magnetic resonance imaging, identification of the 14-3-3 protein in the cerebrospinal fluid, tonsil biopsy and genetic studies have been used for in vivo diagnosis circumventing the need of brain biopsy. Histopathology, however, remains the only conclusive method to reach a confident diagnosis. Unfortunately, despite numerous treatment efforts, prionopathies remain short-lasting and fatal diseases.

  14. Lewy Body Dementia Glossary

    MedlinePlus

    ... brain. Creutzfeldt-Jakob disease : Very rare and fatal degenerative disease of the brain, generally characterized by a rapidly ... the terminal stages of their illness. Huntington’s disease: Degenerative brain disease involving jerky, uncontrolled movements and cognitive impairments in ...

  15. Investigating the Association of ApoE Genotypes with Blood-Brain Barrier Dysfunction Measured by Cerebrospinal Fluid-Serum Albumin Ratio in a Cohort of Patients with Different Types of Dementia

    PubMed Central

    Karch, André; Manthey, Henrike; Ponto, Claudia; Hermann, Peter; Heinemann, Uta; Schmidt, Christian; Zerr, Inga

    2013-01-01

    Background Since more than a decade ApoE is known to be a strong risk factor for Alzheimer's disease (AD); however, molecular pathways mediating this risk are still unclear. In recent years it has been hypothesized that ApoE might play a role in the disintegration of blood-brain barrier (BBB). In the present study we addressed the question if ApoE genotypes might be associated with BBB function measured by albumin ratio (QAlb) in a large cohort of patients with different types of dementia. Methods Five hundred twenty (520) patients with Creutzfeldt-Jakob disease (CJD, n = 350), Alzheimer's disease (n = 71) and cerebral small vessel disease (n = 99) were assessed for their ApoE genotype. BBB function was measured in all patients using QAlb and was compared between ApoE genotypes. Dominant and additive genetic models were assumed in order to investigate the potential effect of ApoE on BBB function. Results We observed no systematic differences in QAlb between ApoE genotypes within the present study. Increased QAlb levels were shown for those without E3 allele in the subgroup of CJD patients when assuming a dominant genetic model (p = 0.035). This could not be confirmed for patients with other forms of dementia (p = 0.234). Discussion Although there was some evidence for a protective effect of E3 alleles in CJD patients, this study does not support the hypothesis of a systematic role of ApoE genotypes in BBB function in individuals with a diagnosis of dementia. Thus, changes in BBB function do not seem to contribute to the increased risk of cognitive decline associated with certain ApoE genotypes. The interpretation of the results of this study must take into account that BBB function was only assessed by measuring QAlb which has been shown to be a good marker for overall BBB integrity but might not reflect all qualities of the barrier. PMID:24386372

  16. The expanding universe of prion diseases.

    PubMed

    Watts, Joel C; Balachandran, Aru; Westaway, David

    2006-03-01

    Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrP(C). Several mammalian species are affected by the diseases, and in the case of "mad cow disease" (BSE) the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases--including human diseases variant Creutzfeldt-Jakob disease (vCJD) and sporadic fatal insomnia (sFI), bovine amyloidotic spongiform encephalopathy (BASE), and Nor98 of sheep--have been identified in the last ten years, and chronic wasting disease (CWD) of North American deer (Odocoileus Specis) and Rocky Mountain elk (Cervus elaphus nelsoni) is undergoing a dramatic spread across North America. While amplification (BSE) and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk) can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of "sporadic" disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded.

  17. The Expanding Universe of Prion Diseases

    PubMed Central

    Watts, Joel C; Balachandran, Aru; Westaway, David

    2006-01-01

    Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrPC. Several mammalian species are affected by the diseases, and in the case of “mad cow disease” (BSE) the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases—including human diseases variant Creutzfeldt-Jakob disease (vCJD) and sporadic fatal insomnia (sFI), bovine amyloidotic spongiform encephalopathy (BASE), and Nor98 of sheep—have been identified in the last ten years, and chronic wasting disease (CWD) of North American deer (Odocoileus Specis) and Rocky Mountain elk (Cervus elaphus nelsoni) is undergoing a dramatic spread across North America. While amplification (BSE) and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk) can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of “sporadic” disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded. PMID:16609731

  18. [Human prion diseases in the Czech Republic].

    PubMed

    Rohan, Z; Rusina, R; Marešová, M; Matěj, R

    2015-09-01

    Human prion diseases are a group of very rare diseases with a unique pathogenesis and, due to an inauspicious prognosis and unavailability of therapy, with fatal consequences. The etiopathogenetic background is the presence of pathologically misfolded prion protein, highly resistant to denaturation, the aggregation and presence of which in the brain tissue causes irreversible neuronal damage. The most frequent prion disease in humans is Creutzfeldt-Jakob disease (CJD) which occurs in sporadic, hereditary/familial, or acquired/infectious/iatrogenic forms. A new form of CJD, variant CJD, is considered to be linked to dietary exposure to beef products from cattle infected with bovine spongiform encephalopathy (BSE) and to infection via blood transfusion. The clinical picture of these diseases is characterized by a rapidly progressing dementia, cerebellar and extrapyramidal symptoms, and rather specific MRI, EEG, and CSF findings. Clinically, the diagnosis is described as possible or probable prion disease and needs to be confirmed by neuropathological or immunological investigation of the brain tissue. Epidemiological data from the Czech Republic spanning the last decade are presented.

  19. Human Prion Disease and Relative Risk Associated with Chronic Wasting Disease

    PubMed Central

    Pape, W. John; Forster, Jeri E.; Anderson, C. Alan; Bosque, Patrick; Miller, Michael W.

    2006-01-01

    The transmission of the prion disease bovine spongiform encephalopathy (BSE) to humans raises concern about chronic wasting disease (CWD), a prion disease of deer and elk. In 7 Colorado counties with high CWD prevalence, 75% of state hunting licenses are issued locally, which suggests that residents consume most regionally harvested game. We used Colorado death certificate data from 1979 through 2001 to evaluate rates of death from the human prion disease Creutzfeldt-Jakob disease (CJD). The relative risk (RR) of CJD for CWD-endemic county residents was not significantly increased (RR 0.81, 95% confidence interval [CI] 0.40–1.63), and the rate of CJD did not increase over time (5-year RR 0.92, 95% CI 0.73–1.16). In Colorado, human prion disease resulting from CWD exposure is rare or nonexistent. However, given uncertainties about the incubation period, exposure, and clinical presentation, the possibility that the CWD agent might cause human disease cannot be eliminated. PMID:17176567

  20. From Prion Diseases to Prion-Like Propagation Mechanisms of Neurodegenerative Diseases

    PubMed Central

    Acquatella-Tran Van Ba, Isabelle; Imberdis, Thibaut; Perrier, Véronique

    2013-01-01

    Prion diseases are fatal neurodegenerative sporadic, inherited, or acquired disorders. In humans, Creutzfeldt-Jakob disease is the most studied prion disease. In animals, the most frequent prion diseases are scrapie in sheep and goat, bovine spongiform encephalopathy in cattle, and the emerging chronic wasting disease in wild and captive deer in North America. The hallmark of prion diseases is the deposition in the brain of PrPSc, an abnormal β-sheet-rich form of the cellular prion protein (PrPC) (Prusiner 1982). According to the prion hypothesis, PrPSc can trigger the autocatalytic conversion of PrPC into PrPSc, presumably in the presence of cofactors (lipids and small RNAs) that have been recently identified. In this review, we will come back to the original works that led to the discovery of prions and to the protein-only hypothesis proposed by Dr. Prusiner. We will then describe the recent reports on mammalian synthetic prions and recombinant prions that strongly support the protein-only hypothesis. The new concept of “deformed templating” regarding a new mechanism of PrPSc formation and replication will be exposed. The review will end with a chapter on the prion-like propagation of other neurodegenerative disorders, such as Alzheimer's and Parkinson's disease and tauopathies. PMID:24222767

  1. Prion diseases and the gastrointestinal tract.

    PubMed

    Davies, G A; Bryant, Adam R; Reynolds, John D; Jirik, Frank R; Sharkey, Keith A

    2006-01-01

    The gastrointestinal (GI) tract plays a central role in the pathogenesis of transmissible spongiform encephalopathies. These are human and animal diseases that include bovine spongiform encephalopathy, scrapie and Creutzfeldt-Jakob disease. They are uniformly fatal neurological diseases, which are characterized by ataxia and vacuolation in the central nervous system. Although they are known to be caused by the conversion of normal cellular prion protein to its infectious conformational isoform (PrPsc) the process by which this isoform is propagated and transported to the brain remains poorly understood. M cells, dendritic cells and possibly enteroendocrine cells are important in the movement of infectious prions across the GI epithelium. From there, PrPsc propagation requires B lymphocytes, dendritic cells and follicular dendritic cells of Peyer's patches. The early accumulation of the disease-causing agent in the plexuses of the enteric nervous system supports the contention that the autonomic nervous system is important in disease transmission. This is further supported by the presence of PrPsc in the ganglia of the parasympathetic and sympathetic nerves that innervate the GI tract. Additionally, the lymphoreticular system has been implicated as the route of transmission from the gut to the brain. Although normal cellular prion protein is found in the enteric nervous system, its role has not been characterized. Further research is required to understand how the cellular components of the gut wall interact to propagate and transmit infectious prions to develop potential therapies that may prevent the progression of transmissible spongiform encephalopathies.

  2. Protein-misfolding diseases and chaperone-based therapeutic approaches.

    PubMed

    Chaudhuri, Tapan K; Paul, Subhankar

    2006-04-01

    A large number of neurodegenerative diseases in humans result from protein misfolding and aggregation. Protein misfolding is believed to be the primary cause of Alzheimer's disease, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, cystic fibrosis, Gaucher's disease and many other degenerative and neurodegenerative disorders. Cellular molecular chaperones, which are ubiquitous, stress-induced proteins, and newly found chemical and pharmacological chaperones have been found to be effective in preventing misfolding of different disease-causing proteins, essentially reducing the severity of several neurodegenerative disorders and many other protein-misfolding diseases. In this review, we discuss the probable mechanisms of several protein-misfolding diseases in humans, as well as therapeutic approaches for countering them. The role of molecular, chemical and pharmacological chaperones in suppressing the effect of protein misfolding-induced consequences in humans is explained in detail. Functional aspects of the different types of chaperones suggest their uses as potential therapeutic agents against different types of degenerative diseases, including neurodegenerative disorders.

  3. Gastrostomy in patients with prion disease.

    PubMed

    Iwasaki, Yasushi; Mori, Keiko; Ito, Masumi; Kawai, Yoshinari; Hoshino, Ken-Ichiro; Kawabata, Yuko; Mimuro, Maya; Yoshida, Mari

    2017-05-04

    Patients with prion diseases can live for long periods of time in a state of akinetic mutism given appropriate management of their symptoms. To study symptom support in these cases, we performed gastrostomies on 3 patients with V180I genetic Creutzfeldt-Jakob disease (CJD) who had become akinetic and mute, and compared them to 14 other similar patients being fed by tube. In the 3 gastrostomy cases, there were no direct complications due to the gastrostomy or tube feeding, nor were there episodes of discontinuation of tube feeding or initiation of continuous drip infusion due to severe complications. Antibiotics were administered for mild infections, a complication of CJD, with 0.2% and 8.8% of the total time after gastrostomy being used for intravenous or transluminal administration, respectively. We compared the present patient series with that of our previous report statistically, and found that patients undergoing gastrostomy required significantly fewer discontinuations of tube feeding than those who did not. No significant difference in antibiotic administration was found between groups, however. It is our conclusion that gastrostomy should be allowed for symptom support in akinetic patients with prion disease, but adequate informed consent must be provided to the patient's family.

  4. Prospects for preventative vaccines against prion diseases.

    PubMed

    Sakaguchi, Suehiro

    2009-01-01

    Emergence of variant type of Creutzfeldt-Jakob disease (vCJD) in humans due to infection from bovine spongiform encephalopathy contaminated beef and recent reports of human-to-human transmission of vCJD via blood transfusion have raised great concern about an epidemic of vCJD. The disease is currently difficult to diagnose during pre-clinical stages and requires a very long incubation period for neurological symptoms to be evident. This therefore suggests that the disease is already latently spreading and that opportunity for infection is thus growing among human populations. Interestingly, passive immunization with antibodies against prion protein (PrP), a major component of the prion infectious agents, was shown to protect mice from infection, indicating the possibility of prion vaccines. However, PrP is a host protein therefore immune tolerance to PrP has hampered development of them. Here, the so far reported attempts to overcome the tolerance to elicit protective immunity to prions are briefly reviewed.

  5. [Systematic review of the therapeutics for prion diseases].

    PubMed

    Sakaguchi, Suehiro

    2009-08-01

    Prion diseases are fatal infectious neurodegenerative disorders; examples include the Creutzfeldt-Jakob disease affecting humans and bovine spongiform encephalopathy in cattle. The causative agents of these diseases--the prions--are thought to consist of the pathogenic isoform of the prion protein PrP(Sc), which is produced by the conformational conversion of the normal isoform PrP(c). Many lines of evidence indicate that the constitutive conversion of PrP(c) to PrP(Sc), resulting in a marked accumulation of PrP(Sc) in the brain, is a central event in the pathogenesis of prion diseases. A large number of compounds have been identified as anti-prion agents and capable of reducing the PrP(Sc) levels in infected cells. Some of these compounds have been found to be partially effective in infected animals, thus resulting in the prolongation of the incubation or survival times and a few of these compounds were or are under clinical trials. However, none of these compounds have proven to be therapeutically effective against this group of diseases. This is probably because (1) these compounds fail to cross the blood-brain barrier and (2) their effectiveness is reduced because they are administered only to patients with clinically advanced disease owing to a lack of diagnostic indicators for presymptomatic individuals. In this communication, we systematically list these anti-prion compounds and summarize their effectiveness and possible mechanisms of action.

  6. Shadoo (Sprn) and prion disease incubation time in mice.

    PubMed

    Lloyd, Sarah E; Grizenkova, Julia; Pota, Hirva; Collinge, John

    2009-06-01

    Prion diseases are transmissible neurodegenerative disorders of mammalian species and include scrapie, bovine spongiform encephalopathy (BSE), and variant Creutzfeldt-Jakob disease (vCJD). The prion protein (PrP) plays a key role in the disease, with coding polymorphism in both human and mouse influencing disease susceptibility and incubation time, respectively. Other genes are also thought to be important and a plausible candidate is Sprn, which encodes the PrP-like protein Shadoo (Sho). Sho is expressed in the adult central nervous system and exhibits neuroprotective activity reminiscent of PrP in an in vitro assay. To investigate the role of Sprn in prion disease incubation time we sequenced the open reading frame (ORF) in a diverse panel of mice and saw little variation except in strains derived from wild-trapped mice. Sequencing the untranslated regions revealed polymorphisms that allowed us to carry out an association study of incubation period in the Northport heterogeneous stock of mice inoculated with Chandler/RML prions. We also examined the expression level of Sprn mRNA in the brains of normal and prion-infected mice and saw no correlation with either genotype or incubation time. We therefore conclude that Sprn does not play a major role in prion disease incubation time in these strains of mice.

  7. Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases.

    PubMed

    Irwin, Michael H; Moos, Walter H; Faller, Douglas V; Steliou, Kosta; Pinkert, Carl A

    2016-05-01

    Preclinical Research In this review, we discuss epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt-Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy. Drug Dev Res 77 : 109-123, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  8. Could ectoparasites act as vectors for prion diseases?

    PubMed

    Lupi, Omar

    2003-06-01

    Prion diseases are rare neurodegenerative diseases of humans and animals with a lethal evolution. Several cell types found on the human skin, including keratinocytes, fibroblasts and lymphocytes, are susceptible to the abnormal infective isoform of the prion protein, which transforms the skin to produce a potential target for prion infection. Iatrogenic transmission of Creutzfeldt-Jakob disease was also recognized after corneal transplants in humans, and scrapie was successfully transmitted to mice after ocular instillation of infected brain tissue, confirming that these new routes, as well as cerebral inoculation and oral ingestion, could be important in prion infections. Animal prion infections, such as scrapie (sheep) and "mad cow disease" (cattle), have shown a pattern of horizontal transmission in farm conditions and several ectoparasites have been shown to harbor prion rods in laboratory experiments. Fly larvae and mites were exposed to brain-infected material and were readily able to transmit scrapie to hamsters. New lines of evidence have confirmed that adult flies are also able to express prion proteins. Because ocular and cerebral myiases and mite infestation are not rare worldwide, and most cases are caused by fly larvae or hay mites that usually affect sheep and cattle, it is important to discuss the possibility that these ectoparasites could eventually act as reservoirs and/or vectors for prion diseases.

  9. Proteinase-activated receptor 2 and disease biomarkers in cerebrospinal fluid in cases with autopsy-confirmed prion diseases and other neurodegenerative diseases.

    PubMed

    Rohan, Zdenek; Smetakova, Magdalena; Kukal, Jaromir; Rusina, Robert; Matej, Radoslav

    2015-03-31

    Proteinase-activated receptor 2 (PAR-2) has been shown to promote both neurotoxic and neuroprotective effects. Similarly, other routinely used nonspecific markers of neuronal damage can be found in cerebrospinal fluid (CSF) and can be used as biomarkers for different neurodegenerative disorders. Using enzyme-linked immunosorbent assays and western blotting we assessed PAR-2, total-tau, phospho-tau, beta-amyloid levels, and protein 14-3-3 in the CSF of former patients who had undergone a neuropathological autopsy after death and who had been definitively diagnosed with a prion or other neurodegenerative disease. We did not find any significant correlation between levels of PAR-2 and other biomarkers, nor did we find any differences in PAR-2 levels between prion diseases and other neurodegenerative conditions. However, we confirmed that very high total-tau levels were significantly associated with definitive prion diagnoses and exhibited greater sensitivity and specificity than protein 14-3-3, which is routinely used as a marker. Our study showed that PAR-2, in CSF, was not specifically altered in prion diseases compared to other neurodegenerative conditions. Our results also confirmed that very high total-tau protein CSF levels were significantly associated with a definitive Creutzfeldt-Jakob disease (CJD) diagnosis and should be routinely tested as a diagnostic marker. Observed individual variability in CSF biomarkers provide invaluable feedback from neuropathological examinations even in "clinically certain" cases.

  10. Prion disease blood test using immunoprecipitation and improved quaking-induced conversion.

    PubMed

    Orrú, Christina D; Wilham, Jason M; Raymond, Lynne D; Kuhn, Franziska; Schroeder, Björn; Raeber, Alex J; Caughey, Byron

    2011-01-01

    A key challenge in managing transmissible spongiform encephalopathies (TSEs) or prion diseases in medicine, agriculture, and wildlife biology is the development of practical tests for prions that are at or below infectious levels. Of particular interest are tests capable of detecting prions in blood components such as plasma, but blood typically has extremely low prion concentrations and contains inhibitors of the most sensitive prion tests. One of the latter tests is quaking-induced conversion (QuIC), which can be as sensitive as in vivo bioassays, but much more rapid, higher throughput, and less expensive. Now we have integrated antibody 15B3-based immunoprecipitation with QuIC reactions to increase sensitivity and isolate prions from inhibitors such as those in plasma samples. Coupling of immunoprecipitation and an improved real-time QuIC reaction dramatically enhanced detection of variant Creutzfeldt-Jakob disease (vCJD) brain tissue diluted into human plasma. Dilutions of 10(14)-fold, containing ~2 attogram (ag) per ml of proteinase K-resistant prion protein, were readily detected, indicating ~10,000-fold greater sensitivity for vCJD brain than has previously been reported. We also discriminated between plasma and serum samples from scrapie-infected and uninfected hamsters, even in early preclinical stages. This combined assay, which we call "enhanced QuIC" (eQuIC), markedly improves prospects for routine detection of low levels of prions in tissues, fluids, or environmental samples. Transmissible spongiform encephalopathies (TSEs) are largely untreatable and are difficult to diagnose definitively prior to irreversible clinical decline or death. The transmissibility of TSEs within and between species highlights the need for practical tests for even the smallest amounts of infectivity. A few sufficiently sensitive in vitro methods have been reported, but most have major limitations that would preclude their use in routine diagnostic or screening applications

  11. Progress and problems in the biology, diagnostics, and therapeutics of prion diseases

    PubMed Central

    Aguzzi, Adriano; Heikenwalder, Mathias; Miele, Gino

    2004-01-01

    The term “prion” was introduced by Stanley Prusiner in 1982 to describe the atypical infectious agent that causes transmissible spongiform encephalopathies, a group of infectious neurodegenerative diseases that include scrapie in sheep, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. Over the past twenty years, the word “prion” has been taken to signify various subtly different concepts. In this article, we refer to the prion as the transmissible principle underlying prion diseases, without necessarily implying any specific biochemical or structural identity. When Prusiner started his seminal work, the study of transmissible spongiform encephalopathies was undertaken by only a handful of scientists. Since that time, the “mad cow” crisis has put prion diseases on the agenda of both politicians and the media. Significant progress has been made in prion disease research, and many aspects of prion pathogenesis are now understood. And yet the diagnostic procedures available for prion diseases are not nearly as sensitive as they ought to be, and no therapeutic intervention has been shown to reliably affect the course of the diseases. This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields. PMID:15254579

  12. Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation

    PubMed Central

    Lau, Agnes; McDonald, Alex; Daude, Nathalie; Mays, Charles E; Walter, Eric D; Aglietti, Robin; Mercer, Robert CC; Wohlgemuth, Serene; van der Merwe, Jacques; Yang, Jing; Gapeshina, Hristina; Kim, Chae; Grams, Jennifer; Shi, Beipei; Wille, Holger; Balachandran, Aru; Schmitt-Ulms, Gerold; Safar, Jiri G; Millhauser, Glenn L; Westaway, David

    2015-01-01

    The cellular prion protein (PrPC) comprises a natively unstructured N-terminal domain, including a metal-binding octarepeat region (OR) and a linker, followed by a C-terminal domain that misfolds to form PrPSc in Creutzfeldt-Jakob disease. PrPC β-endoproteolysis to the C2 fragment allows PrPSc formation, while α-endoproteolysis blocks production. To examine the OR, we used structure-directed design to make novel alleles, ‘S1’ and ‘S3’, locking this region in extended or compact conformations, respectively. S1 and S3 PrP resembled WT PrP in supporting peripheral nerve myelination. Prion-infected S1 and S3 transgenic mice both accumulated similar low levels of PrPSc and infectious prion particles, but differed in their clinical presentation. Unexpectedly, S3 PrP overproduced C2 fragment in the brain by a mechanism distinct from metal-catalysed hydrolysis reported previously. OR flexibility is concluded to impact diverse biological endpoints; it is a salient variable in infectious disease paradigms and modulates how the levels of PrPSc and infectivity can either uncouple or engage to drive the onset of clinical disease. PMID:25661904

  13. The Leeuwenhoek Lecture 2001. Animal origins of human infectious disease.

    PubMed

    Weiss, R A

    2001-06-29

    Since time immemorial animals have been a major source of human infectious disease. Certain infections like rabies are recognized as zoonoses caused in each case by direct animal-to-human transmission. Others like measles became independently sustained with the human population so that the causative virus has diverged from its animal progenitor. Recent examples of direct zoonoses are variant Creutzfeldt-Jakob disease arising from bovine spongiform encephalopathy, and the H5N1 avian influenza outbreak in Hong Kong. Epidemics of recent animal origin are the 1918-1919 influenza pandemic, and acquired immune deficiency syndrome caused by human immunodeficiency virus (HIV). Some retroviruses jump into and out of the chromosomal DNA of the host germline, so that they oscillate between being inherited Mendelian traits or infectious agents in different species. Will new procedures like animal-to-human transplants unleash further infections? Do microbes become more virulent upon cross-species transfer? Are animal microbes a threat as biological weapons? Will the vast reservoir of immunodeficient hosts due to the HIV pandemic provide conditions permissive for sporadic zoonoses to take off as human-to-human transmissible diseases? Do human infections now pose a threat to endangered primates? These questions are addressed in this lecture.

  14. Identifying Unstable Regions of Proteins Involved in Misfolding Diseases

    NASA Astrophysics Data System (ADS)

    Guest, Will; Cashman, Neil; Plotkin, Steven

    2009-05-01

    Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and all-atoms molecular dynamics. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

  15. Molecular pathogenesis of sporadic prion diseases in man.

    PubMed

    Safar, Jiri G

    2012-01-01

    The yeast, fungal and mammalian prions determine heritable and infectious traits that are encoded in alternative conformations of proteins. They cause lethal sporadic, familial and infectious neurodegenerative conditions in man, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), kuru, sporadic fatal insomnia (SFI) and likely variable protease-sensitive prionopathy (VPSPr). The most prevalent of human prion diseases is sporadic (s)CJD. Recent advances in amplification and detection of prions led to considerable optimism that early and possibly preclinical diagnosis and therapy might become a reality. Although several drugs have already been tested in small numbers of sCJD patients, there is no clear evidence of any agent's efficacy. Therefore, it remains crucial to determine the full spectrum of sCJD prion strains and the conformational features in the pathogenic human prion protein governing replication of sCJD prions. Research in this direction is essential for the rational development of diagnostic as well as therapeutic strategies. Moreover, there is growing recognition that fundamental processes involved in human prion propagation - intercellular induction of protein misfolding and seeded aggregation of misfolded host proteins - are of far wider significance. This insight leads to new avenues of research in the ever-widening spectrum of age-related human neurodegenerative diseases that are caused by protein misfolding and that pose a major challenge for healthcare.

  16. Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Correlation of Histopathology and MRI in Prion Disease.

    PubMed

    Mente, Karin P; O'Donnell, James K; Jones, Stephen E; Cohen, Mark L; Thompson, Nicolas R; Bizzi, Alberto; Gambetti, Pierluigi; Safar, Jiri G; Appleby, Brian S

    2017-01-01

    Creutzfeldt-Jakob disease (CJD) and other prion diseases are rapidly progressive spongiform encephalopathies that are invariably fatal. Clinical features and magnetic resonance imaging, electroencephalogram, and cerebrospinal fluid abnormalities may suggest prion disease, but a definitive diagnosis can only be made by means of neuropathologic examination. Fluorodeoxyglucose positron emission tomography (FDG-PET) is not routinely used to evaluate patients with suspected prion disease. This study includes 11 cases of definite prion disease in which FDG-PET scans were obtained. There were 8 sporadic CJD cases, 2 genetic CJD cases, and 1 fatal familial insomnia case. Automated FDG-PET analysis revealed parietal region hypometabolism in all cases. Surprisingly, limbic and mesolimbic hypermetabolism were also present in the majority of cases. When FDG-PET hypometabolism was compared with neuropathologic changes (neuronal loss, astrocytosis, spongiosis), hypometabolism was predictive of neuropathology in 80.6% of cortical regions versus 17.6% of subcortical regions. The odds of neuropathologic changes were 2.1 times higher in cortical regions than subcortical regions (P=0.0265). A similar discordance between cortical and subcortical regions was observed between FDG-PET hypometabolism and magnetic resonance imaging diffusion weighted imaging hyperintensity. This study shows that there may be a relationship between FDG-PET hypometabolism and neuropathology in cortical regions in prion disease but it is unlikely to be helpful for diagnosis.

  17. Role of zinc and copper ions in the pathogenetic mechanisms of Alzheimer's and Parkinson's diseases.

    PubMed

    Stelmashook, E V; Isaev, N K; Genrikhs, E E; Amelkina, G A; Khaspekov, L G; Skrebitsky, V G; Illarioshkin, S N

    2014-05-01

    Disbalance of zinc (Zn2+) and copper (Cu2+) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as multisystem atrophy, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Wilson-Konovalov disease, Alzheimer's disease, and Parkinson's disease. Among these, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent age-related neurodegenerative pathologies with disorders in Zn2+ and Cu2+ homeostasis playing a pivotal role in the mechanisms of pathogenesis. In this review we generalized and systematized current literature data concerning this problem. The interactions of Zn2+ and Cu2+ with amyloid precursor protein (APP), β-amyloid (Abeta), tau-protein, metallothioneins, and GSK3β are considered, as well as the role of these interactions in the generation of free radicals in AD and PD. Analysis of the literature suggests that the main factors of AD and PD pathogenesis (oxidative stress, structural disorders and aggregation of proteins, mitochondrial dysfunction, energy deficiency) that initiate a cascade of events resulting finally in the dysfunction of neuronal networks are mediated by the disbalance of Zn2+ and Cu2+.

  18. HECTD2 Is Associated with Susceptibility to Mouse and Human Prion Disease

    PubMed Central

    Lloyd, Sarah E.; Maytham, Emma G.; Pota, Hirva; Grizenkova, Julia; Molou, Eleni; Uphill, James; Hummerich, Holger; Whitfield, Jerome; Alpers, Michael P.; Mead, Simon; Collinge, John

    2009-01-01

    Prion diseases are fatal transmissible neurodegenerative disorders, which include Scrapie, Bovine Spongiform Encephalopathy (BSE), Creutzfeldt-Jakob Disease (CJD), and kuru. They are characterised by a prolonged clinically silent incubation period, variation in which is determined by many factors, including genetic background. We have used a heterogeneous stock of mice to identify Hectd2, an E3 ubiquitin ligase, as a quantitative trait gene for prion disease incubation time in mice. Further, we report an association between HECTD2 haplotypes and susceptibility to the acquired human prion diseases, vCJD and kuru. We report a genotype-associated differential expression of Hectd2 mRNA in mouse brains and human lymphocytes and a significant up-regulation of transcript in mice at the terminal stage of prion disease. Although the substrate of HECTD2 is unknown, these data highlight the importance of proteosome-directed protein degradation in neurodegeneration. This is the first demonstration of a mouse quantitative trait gene that also influences susceptibility to human prion diseases. Characterisation of such genes is key to understanding human risk and the molecular basis of incubation periods. PMID:19214206

  19. HECTD2 is associated with susceptibility to mouse and human prion disease.

    PubMed

    Lloyd, Sarah E; Maytham, Emma G; Pota, Hirva; Grizenkova, Julia; Molou, Eleni; Uphill, James; Hummerich, Holger; Whitfield, Jerome; Alpers, Michael P; Mead, Simon; Collinge, John

    2009-02-01

    Prion diseases are fatal transmissible neurodegenerative disorders, which include Scrapie, Bovine Spongiform Encephalopathy (BSE), Creutzfeldt-Jakob Disease (CJD), and kuru. They are characterised by a prolonged clinically silent incubation period, variation in which is determined by many factors, including genetic background. We have used a heterogeneous stock of mice to identify Hectd2, an E3 ubiquitin ligase, as a quantitative trait gene for prion disease incubation time in mice. Further, we report an association between HECTD2 haplotypes and susceptibility to the acquired human prion diseases, vCJD and kuru. We report a genotype-associated differential expression of Hectd2 mRNA in mouse brains and human lymphocytes and a significant up-regulation of transcript in mice at the terminal stage of prion disease. Although the substrate of HECTD2 is unknown, these data highlight the importance of proteosome-directed protein degradation in neurodegeneration. This is the first demonstration of a mouse quantitative trait gene that also influences susceptibility to human prion diseases. Characterisation of such genes is key to understanding human risk and the molecular basis of incubation periods.

  20. The influence of PRNP polymorphisms on human prion disease susceptibility: an update.

    PubMed

    Kobayashi, Atsushi; Teruya, Kenta; Matsuura, Yuichi; Shirai, Tsuyoshi; Nakamura, Yoshikazu; Yamada, Masahito; Mizusawa, Hidehiro; Mohri, Shirou; Kitamoto, Tetsuyuki

    2015-08-01

    Two normally occurring polymorphisms of the human PRNP gene, methionine (M)/valine (V) at codon 129 and glutamic acid (E)/lysine (K) at codon 219, can affect the susceptibility to prion diseases. It has long been recognized that 129M/M homozygotes are overrepresented in sporadic Creutzfeldt-Jakob disease (CJD) patients and variant CJD patients, whereas 219E/K heterozygotes are absent in sporadic CJD patients. In addition to these pioneering findings, recent progress in experimental transmission studies and worldwide surveillance of prion diseases have identified novel relationships between the PRNP polymorphisms and the prion disease susceptibility. For example, although 219E/K heterozygosity confers resistance against the development of sporadic CJD, this genotype is not entirely protective against acquired forms (iatrogenic CJD and variant CJD) or genetic forms (genetic CJD and Gerstmann-Sträussler-Scheinker syndrome) of prion diseases. In addition, 129M/V heterozygotes predispose to genetic CJD caused by a pathogenic PRNP mutation at codon 180. These findings show that the effects of the PRNP polymorphisms may be more complicated than previously thought. This review aims to summarize recent advances in our knowledge about the influence of the PRNP polymorphisms on the prion disease susceptibility.

  1. [Patient with Creutzfeld-Jakob disease - a case report].

    PubMed

    Pastuszak, Żanna; Tomczykiewicz, Kazimierz; Stępień, Adam; Piusińska-Macoch, Renata; Klimczuk, Joanna; Rolewska, Agnieszka; Galbarczyk, Dariusz

    2017-02-20

    Creutzfeldt-Jakob disease (CJD) is a rare syndrome of central nervous system caused by infectious protein called prion. There are four types of CJD: sporadic (sCJD), familial (fCJD), jatrogenic (jCJD) and variant (vCJD). The most frequent symptoms are rapidly progressing dementia, mioclonias, akinetic mutism and signs of cerebellum dysfunction. In sCJD, MRI often shows high signal intensity in the putamen and caudate nucleus on T2-weighted images while in vCJD pulvinar sign is often observed. 70% patients with CJD often has characteristic generalized periodic sharp wave pattern in electroencephalography. In case of 90% patients with CJD 14-3-3 protein is present in cerebrospinal fluid. Neuropathological studies play an important role in disease diagnosis. CJD incidence is 0.5-1 on 1000000 people but some cases can be undiagnosed. Presented study is a description of woman with sCJD confirmed with histopathological study. Since childhood patient had psychotic symptoms and behavior disturbances. Patient wasn't diagnosed due to this symptoms. Few months before admission to hospital her condition was getting worse. Symptoms of cerebellum, pyramidal and extrapyramidal system occurred. In cerebrospinal fluid 14-3-3 protein was detected. In EEG and MRI changes specific for sCJD was observed. After three months patient died.

  2. Preclinical detection of infectivity and disease-specific PrP in blood throughout the incubation period of prion disease

    PubMed Central

    Sawyer, Elizabeth B.; Edgeworth, Julie Ann; Thomas, Claire; Collinge, John; Jackson, Graham S.

    2015-01-01

    Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disorder characterised by accumulation of pathological isoforms of the prion protein, PrP. Although cases of clinical vCJD are rare, there is evidence there may be tens of thousands of infectious carriers in the United Kingdom alone. This raises concern about the potential for perpetuation of infection via medical procedures, in particular transfusion of contaminated blood products. Accurate biochemical detection of prion infection is crucial to mitigate risk and we have previously reported a blood assay for vCJD. This assay is sensitive for abnormal PrP conformers at the earliest stages of preclinical prion disease in mice and precedes the maximum infectious titre in blood. Not only does this support the possibility of screening asymptomatic individuals, it will also facilitate the elucidation of the complex relationship that exists between the ensemble of abnormal PrP conformers present in blood and the relationship to infectivity. PMID:26631638

  3. Therapy in prion diseases.

    PubMed

    Forloni, Gianluigi; Artuso, Vladimiro; Roiter, Ignazio; Morbin, Michela; Tagliavini, Fabrizio

    2013-01-01

    In the last two decades, knowledge of the neurobiology of prion diseases or transmissible spongiform encephalopathies (TSE) has significantly advanced, but a successful therapy to stop or delay the progression of these disorders remains one of the most challenging goals of biomedical research. Several obstacles to this achievement are in common with other neurodegenerative disorders: difficulties to move from experimental level to clinical stage; appropriate timing of intervention; correct set up of clinical trial. Also in terms of molecular bases of disease, TSE and the other neurodegenerative disorders associated with protein misfolding such as Alzheimer, Parkinson and Huntington diseases, share a central pathogenic role of soluble small aggregates, named oligomers, considered the culprit of neuronal dysfunction: accordingly, these disorders could by termed oligomeropathies. However, the rapid progression of TSE, together with their clinical and molecular heterogeneity, make the therapeutic approach particularly problematic. The main target of the antiprion strategy has been the pathological form of the cellular prion protein (PrP(C)) termed PrP(Sc), invariably associated with the diseases. Several compounds have been found to affect PrP(Sc) formation or enhance its clearance in in vitro models, and prolong survival in experimental animals. However, few of them such as quinacrine and pentosan polysulfate have reached the clinical evaluation; more recently, we have conducted a clinical trial with doxycycline in patients with Creutzfeldt-Jakob disease without satisfactory results. In experimental conditions, active and passive immunization with antibodies against PrP and mucosal vaccination have shown to protect from peripheral infection. Other studies have proposed new potentially effective molecules targeting PrP oligomers. Furthermore, the possibility to interfere with PrP(C) to PrP(Sc) conversion by an active control of PrP(C) is another interesting approach

  4. Novel strain properties distinguishing sporadic prion diseases sharing prion protein genotype and prion type

    PubMed Central

    Cracco, Laura; Notari, Silvio; Cali, Ignazio; Sy, Man-Sun; Chen, Shu G.; Cohen, Mark L.; Ghetti, Bernardino; Appleby, Brian S.; Zou, Wen-Quan; Caughey, Byron; Safar, Jiri G.; Gambetti, Pierluigi

    2017-01-01

    In most human sporadic prion diseases the phenotype is consistently associated with specific pairings of the genotype at codon 129 of the prion protein gene and conformational properties of the scrapie PrP (PrPSc) grossly identified types 1 and 2. This association suggests that the 129 genotype favours the selection of a distinct strain that in turn determines the phenotype. However, this mechanism cannot play a role in the phenotype determination of sporadic fatal insomnia (sFI) and a subtype of sporadic Creutzfeldt-Jakob disease (sCJD) identified as sCJDMM2, which share 129 MM genotype and PrPSc type 2 but are associated with quite distinct phenotypes. Our detailed comparative study of the PrPSc conformers has revealed major differences between the two diseases, which preferentially involve the PrPSc component that is sensitive to digestion with proteases (senPrPSc) and to a lesser extent the resistant component (resPrPSc). We conclude that these variations are consistent with two distinct strains in sFI and sCJDMM2, and that the rarer sFI is the result of a variant strain selection pathway that might be favoured by a different brain site of initial PrPSc formation in the two diseases. PMID:28091514

  5. Phosphatidylinositol-Glycan-Phospholipase D Is Involved in Neurodegeneration in Prion Disease

    PubMed Central

    Jin, Jae-Kwang; Jang, Byungki; Jin, Hyoung Tae; Choi, Eun-Kyoung; Jung, Cha-Gyun; Akatsu, Hiroyasu; Kim, Jae-Il; Carp, Richard I.; Kim, Yong-Sun

    2015-01-01

    PrPSc is formed from a normal glycosylphosphatidylinositol (GPI)-anchored prion protein (PrPC) by a posttranslational modification. Most GPI-anchored proteins have been shown to be cleaved by GPI phospholipases. Recently, GPI-phospholipase D (GPI-PLD) was shown to be a strictly specific enzyme for GPI anchors. To investigate the involvement of GPI-PLD in the processes of neurodegeneration in prion diseases, we examined the mRNA and protein expression levels of GPI-PLD in the brains of a prion animal model (scrapie), and in both the brains and cerebrospinal fluids (CSF) of sporadic and familial Creutzfeldt-Jakob disease (CJD) patients. We found that compared with controls, the expression of GPI-PLD was dramatically down-regulated in the brains of scrapie-infected mice, especially in the caveolin-enriched membrane fractions. Interestingly, the observed decrease in GPI-PLD expression levels began at the same time that PrPSc began to accumulate in the infected brains and this decrease was also observed in both the brain and CSF of CJD patients; however, no differences in expression were observed in either the brains or CSF specimens from Alzheimer’s disease patients. Taken together, these results suggest that the down-regulation of GPI-PLD protein may be involved in prion propagation in the brains of prion diseases. PMID:25867459

  6. Spatial correlation between the prevalence of transmissible spongiform diseases and British soil geochemistry.

    PubMed

    Imrie, C E; Korre, A; Munoz-Melendez, G

    2009-02-01

    Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurological conditions affecting a number of mammals, including sheep and goats (scrapie), cows (BSE), and humans (Creutzfeldt-Jakob disease). The diseases are widely believed to be caused by the misfolding of the normal prion protein to a pathological isoform, which is thought to act as an infectious agent. Outbreaks of the disease are commonly attributed to contaminated feed and genetic susceptibility. However, the implication of copper and manganese in the pathology of the disease, and its apparent geographical clustering, have prompted suggestions of a link with trace elements in the environment. Nevertheless, studies of soils at regional scales have failed to provide evidence of an environmental risk factor. This study uses geostatistical techniques to investigate the correlations between the distribution of TSE prevalence and soil geochemical variables across the UK according to different spatial scales. A similar spatial pattern in scrapie and BSE occurrence is identified, which may be linked with increasing pH and total organic carbon, and decreasing iodine concentration. However, the pattern also resembles that of the density of dairy farming. Nevertheless, despite the low spatial resolution of the TSE data available for this study, the fact that significant correlations are detected indicates there is a possibility of a link between soil geochemistry, scrapie, and BSE. It is suggested that further investigations of the prevalence of TSE and environmental exposure to trace metals should take into account the factors affecting their bioavailability.

  7. Atypical sporadic CJD-MM phenotype with white matter kuru plaques associated with intranuclear inclusion body and argyrophilic grain disease.

    PubMed

    Berghoff, Anna S; Trummert, Anita; Unterberger, Ursula; Ströbel, Thomas; Hortobágyi, Tibor; Kovacs, Gabor G

    2015-08-01

    We describe an atypical neuropathological phenotype of sporadic Creutzfeldt-Jakob disease in a 76-year-old man. The clinical symptoms were characterized by progressive dementia, gait ataxia, rigidity and urinary incontinence. The disease duration was 6 weeks. MRI did not show prominent atrophy or hyperintensities in cortical areas, striatum or thalamus. Biomarker examination of the cerebrospinal fluid deviated from that seen in pure Alzheimer's disease. Triphasic waves in the EEG were detected only later in the disease course, while 14-3-3 assay was positive. PRNP genotyping revealed methionine homozygosity (MM) at codon 129. Neuropathology showed classical CJD changes corresponding to the MM type 1 cases. However, a striking feature was the presence of abundant kuru-type plaques in the white matter. This rare morphology was associated with neuropathological signs of intranuclear inclusion body disease and advanced stage of argyrophilic grain disease. These alterations did not show correlation with each other, thus seemed to develop independently. This case further highlights the complexity of neuropathological alterations in the ageing brain. © 2015 Japanese Society of Neuropathology.

  8. Reversible symptoms and clearance of mutant prion protein in an inducible model of a genetic prion disease in Drosophila melanogaster.

    PubMed

    Murali, A; Maue, R A; Dolph, P J

    2014-07-01

    Prion diseases are progressive disorders that affect the central nervous system leading to memory loss, personality changes, ataxia and neurodegeneration. In humans, these disorders include Creutzfeldt-Jakob disease, kuru and Gerstmann-Straüssler-Scheinker (GSS) syndrome, the latter being a dominantly inherited prion disease associated with missense mutations in the gene that codes for the prion protein. The exact mechanism by which mutant prion proteins affect the central nervous system and cause neurological disease is not well understood. We have generated an inducible model of GSS disease in Drosophila melanogaster by temporally expressing a misfolded form of the murine prion protein in cholinergic neurons. Flies accumulating this mutant protein develop motor abnormalities which are associated with electrophysiological defects in cholinergic neurons. We find that, upon blocking the expression of the mutant protein, both behavioral and electrophysiological defects can be reversed. This represents the first case of reversibility reported in a model of genetic prion disease. Additionally, we observe that endogenous mechanisms exist within Drosophila that are capable of clearing the accumulated prion protein.

  9. Studies of the aggregation of mutant proteins in vitro provide insights into the genetics of amyloid diseases.

    PubMed

    Chiti, Fabrizio; Calamai, Martino; Taddei, Niccolo; Stefani, Massimo; Ramponi, Giampietro; Dobson, Christopher M

    2002-12-10

    Protein aggregation and the formation of highly insoluble amyloid structures is associated with a range of debilitating human conditions, which include Alzheimer's disease, Parkinson's disease, and the Creutzfeldt-Jakob disease. Muscle acylphosphatase (AcP) has already provided significant insights into mutational changes that modulate amyloid formation. In the present paper, we have used this system to investigate the effects of mutations that modify the charge state of a protein without affecting significantly the hydrophobicity or secondary structural propensities of the polypeptide chain. A highly significant inverse correlation was found to exist between the rates of aggregation of the protein variants under denaturing conditions and their overall net charge. This result indicates that aggregation is generally favored by mutations that bring the net charge of the protein closer to neutrality. In light of this finding, we have analyzed natural mutations associated with familial forms of amyloid diseases that involve alteration of the net charge of the proteins or protein fragments associated with the diseases. Sixteen mutations have been identified for which the mechanism of action that causes the pathological condition is not yet known or fully understood. Remarkably, 14 of these 16 mutations cause the net charge of the corresponding peptide or protein that converts into amyloid deposits to be reduced. This result suggests that charge has been a key parameter in molecular evolution to ensure the avoidance of protein aggregation and identifies reduction of the net charge as an important determinant in at least some forms of protein deposition diseases.

  10. Transgenic fatal familial insomnia mice indicate prion infectivity-independent mechanisms of pathogenesis and phenotypic expression of disease.

    PubMed

    Bouybayoune, Ihssane; Mantovani, Susanna; Del Gallo, Federico; Bertani, Ilaria; Restelli, Elena; Comerio, Liliana; Tapella, Laura; Baracchi, Francesca; Fernández-Borges, Natalia; Mangieri, Michela; Bisighini, Cinzia; Beznoussenko, Galina V; Paladini, Alessandra; Balducci, Claudia; Micotti, Edoardo; Forloni, Gianluigi; Castilla, Joaquín; Fiordaliso, Fabio; Tagliavini, Fabrizio; Imeri, Luca; Chiesa, Roberto

    2015-04-01

    Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg) mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD) mice modeling CJD178. No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype.

  11. Transgenic Fatal Familial Insomnia Mice Indicate Prion Infectivity-Independent Mechanisms of Pathogenesis and Phenotypic Expression of Disease

    PubMed Central

    Bouybayoune, Ihssane; Mantovani, Susanna; Del Gallo, Federico; Bertani, Ilaria; Restelli, Elena; Comerio, Liliana; Tapella, Laura; Baracchi, Francesca; Fernández-Borges, Natalia; Mangieri, Michela; Bisighini, Cinzia; Beznoussenko, Galina V.; Paladini, Alessandra; Balducci, Claudia; Micotti, Edoardo; Forloni, Gianluigi; Castilla, Joaquín; Fiordaliso, Fabio; Tagliavini, Fabrizio; Imeri, Luca; Chiesa, Roberto

    2015-01-01

    Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg) mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD) mice modeling CJD178. No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype. PMID:25880443

  12. Highly sensitive rapid fluorescence detection of protein residues on surgical instruments

    NASA Astrophysics Data System (ADS)

    Kovalev, Valeri I.; Bartona, James S.; Richardson, Patricia R.; Jones, Anita C.

    2006-07-01

    There is a risk of contamination of surgical instruments by infectious protein residues, in particular, prions which are the agents for Creutzfeldt-Jakob Disease in humans. They are exceptionally resistant to conventional sterilization, therefore it is important to detect their presence as contaminants so that alternative cleaning procedures can be applied. We describe the development of an optimized detection system for fluorescently labelled protein, suitable for in-hospital use. We show that under optimum conditions the technique can detect ~10 attomole/cm2 with a scan speed of ~3-10 cm2/s of the test instrument's surface. A theoretical analysis and experimental measurements will be discussed.

  13. Medicinal and other products and human and animal transmissible spongiform encephalopathies: memorandum from a WHO meeting.

    PubMed Central

    1997-01-01

    The report in March 1996 of 10 human cases of a novel from of Creutzfeldt-Jakob disease in the United Kingdom, and its possible link to the agent that causes bovine spongiform encephalopathy (BSE), raises many questions about the safety of animal-derived products and by-products entering the food chain or being used in medicine. This Memorandum updates the preventive measures put forward in 1991 to minimize the risks associated with the use of bovine-derived materials in medicinal products and medical devices. PMID:9509622

  14. Human prion protein sequence elements impede cross-species chronic wasting disease transmission

    PubMed Central

    Kurt, Timothy D.; Jiang, Lin; Fernández-Borges, Natalia; Bett, Cyrus; Liu, Jun; Yang, Tom; Spraker, Terry R.; Castilla, Joaquín; Eisenberg, David; Kong, Qingzhong; Sigurdson, Christina J.

    2015-01-01

    Chronic wasting disease (CWD) is a fatal prion disease of North American deer and elk and poses an unclear risk for transmission to humans. Human exposure to CWD occurs through hunting activities and consumption of venison from prion-infected animals. Although the amino acid residues of the prion protein (PrP) that prevent or permit human CWD infection are unknown, NMR-based structural studies suggest that the β2-α2 loop (residues 165–175) may impact species barriers. Here we sought to define PrP sequence determinants that affect CWD transmission to humans. We engineered transgenic mice that express human PrP with four amino acid substitutions that result in expression of PrP with a β2-α2 loop (residues 165–175) that exactly matches that of elk PrP. Compared with transgenic mice expressing unaltered human PrP, mice expressing the human-elk chimeric PrP were highly susceptible to elk and deer CWD prions but were concurrently less susceptible to human Creutzfeldt-Jakob disease prions. A systematic in vitro survey of amino acid differences between humans and cervids identified two additional residues that impacted CWD conversion of human PrP. This work identifies amino acids that constitute a substantial structural barrier for CWD transmission to humans and helps illuminate the molecular requirements for cross-species prion transmission. PMID:25705888

  15. Structure-Based Prediction of Unstable Regions in Proteins: Applications to Protein Misfolding Diseases

    NASA Astrophysics Data System (ADS)

    Guest, Will; Cashman, Neil; Plotkin, Steven

    2009-03-01

    Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and solution of the Poisson-Boltzmann equation. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

  16. Human prion protein sequence elements impede cross-species chronic wasting disease transmission.

    PubMed

    Kurt, Timothy D; Jiang, Lin; Fernández-Borges, Natalia; Bett, Cyrus; Liu, Jun; Yang, Tom; Spraker, Terry R; Castilla, Joaquín; Eisenberg, David; Kong, Qingzhong; Sigurdson, Christina J

    2015-04-01

    Chronic wasting disease (CWD) is a fatal prion disease of North American deer and elk and poses an unclear risk for transmission to humans. Human exposure to CWD occurs through hunting activities and consumption of venison from prion-infected animals. Although the amino acid residues of the prion protein (PrP) that prevent or permit human CWD infection are unknown, NMR-based structural studies suggest that the β2-α2 loop (residues 165-175) may impact species barriers. Here we sought to define PrP sequence determinants that affect CWD transmission to humans. We engineered transgenic mice that express human PrP with four amino acid substitutions that result in expression of PrP with a β2-α2 loop (residues 165-175) that exactly matches that of elk PrP. Compared with transgenic mice expressing unaltered human PrP, mice expressing the human-elk chimeric PrP were highly susceptible to elk and deer CWD prions but were concurrently less susceptible to human Creutzfeldt-Jakob disease prions. A systematic in vitro survey of amino acid differences between humans and cervids identified two additional residues that impacted CWD conversion of human PrP. This work identifies amino acids that constitute a substantial structural barrier for CWD transmission to humans and helps illuminate the molecular requirements for cross-species prion transmission.

  17. Anterior-posterior and lateral hemispheric alterations in cortical glucose utilization in Alzheimer's disease

    SciTech Connect

    Friedland, T.F.; Budinger, T.F.; Jaqust, W.J.; Yano, Y.; Huesman, R.H.; Knittel, B.; Koss, E.; Ober, B.A.

    1984-01-01

    The anatomical and chemical features of Alzheimer's disease (AD) are not distributed evenly throughout the brain. However, the nature of this focality has not been well established in vivo. Dynamic studies using the Donner 280-Crystal Positron Tomograph with (F-18)2-fluorodeoxyglucose were performed in 17 subjects meeting current research criteria for AD, and in 7 healthy age-matched control subjects. Glucose metabolic rates in the temporal-parietal cortex are 27% lower in AD than in controls. Ratios of activity density reveal consistently lower metabolic rates in temporal-parietal than frontal cortex in the AD group, while healthy aged subjects have equal metabolic rates in the two areas. Similar findings have been reported by other laboratories. A major finding is a striking lateral asymmetry of cortical metabolism in AD which does not favor either hemisphere. (The asymmetry is 13% in the AD group, 3% in controls, p<.005.) This has not been previously reported in AD. The consistency with which anterior-posterior metabolic differences are found in AD suggests that the focality of the metabolic changes may be used to develop a noninvasive diagnostic test for the disorder. The metabolic asymmetry in AD may be compared to the clinical and pathological asymmetry found in Creutzfeldt-Jakob disease, and may represent an additional link between AD and the subacute spongiform encephalopathies.

  18. An antibody to the aggregated synthetic prion protein peptide (PrP106-126) selectively recognizes disease-associated prion protein (PrP) from human brain specimens.

    PubMed

    Jones, Michael; Wight, Darren; McLoughlin, Victoria; Norrby, Katherine; Ironside, James W; Connolly, John G; Farquhar, Christine F; MacGregor, Ian R; Head, Mark W

    2009-04-01

    Human prion diseases are characterized by the conversion of the normal host cellular prion protein (PrP(C)) into an abnormal misfolded form [disease-associated prion protein (PrP(Sc))]. Antibodies that are capable of distinguishing between PrP(C) and PrP(Sc) may prove to be useful, not only for the diagnosis of these diseases, but also for a better understanding of the molecular mechanisms involved in disease pathogenesis. In an attempt to produce such antibodies, we immunized mice with an aggregated peptide spanning amino acid residues 106 to 126 of human PrP (PrP106-126). We were able to isolate and single cell clone a hybridoma cell line (P1:1) which secreted an IgM isotype antibody [monoclonal antibody (mAb P1:1)] that recognized the aggregated, but not the monomeric form of the immunogen. When used in immunoprecipitation assays, the antibody did not recognize normal PrP(C) from non-prion disease brain specimens, but did selectively immunoprecipitate full-length PrP(Sc) from cases of variant and sporadic Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker disease. These results suggest that P1:1 recognizes an epitope formed during the structural rearrangement or aggregation of the PrP that is common to the major PrP(Sc) types found in the most common forms of human prion disease.

  19. The impact of social amplification and attenuation of risk and the public reaction to mad cow disease in Canada.

    PubMed

    Lewis, Roxanne E; Tyshenko, Michael G

    2009-05-01

    Following the detection of bovine spongiform encephalopathy (BSE) in Canada, and subsequently in the United States, confidence in the safety of beef products remained high. Consumers actually increased their consumption of beef slightly after the news of an increased risk from mad cow disease, which has been interpreted as public support for beef farmers and confidence in government regulators. The Canadian public showed a markedly different reaction to the news of domestic BSE than the furious and panicked responses observed in the United Kingdom, Germany, and Japan. Using the social amplification of risk framework, we show that, while other countries displayed social amplification of risk, Canada experienced a social attenuation of risk. The attenuated reaction in Canada toward mad cow disease and increased human health risks from variant Creutzfeldt-Jakob disease (vCJD) was due to the social context at the time when BSE was discovered domestically. Mortality, morbidity, and psychosocial impacts resulting from other major events such as severe acute respiratory syndrome (SARS), West Nile virus (WNV), and the U.S.-Iraq war made the theoretical risks of BSE and vCJD a lower priority, reducing its concern as a risk issue.

  20. Transgenic mice recapitulate the phenotypic heterogeneity of genetic prion diseases without developing prion infectivity: Role of intracellular PrP retention in neurotoxicity

    PubMed Central

    Chiesa, Roberto; Restelli, Elena; Comerio, Liliana; Del Gallo, Federico; Imeri, Luca

    2016-01-01

    abstract Genetic prion diseases are degenerative brain disorders caused by mutations in the gene encoding the prion protein (PrP). Different PrP mutations cause different diseases, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome and fatal familial insomnia (FFI). The reason for this variability is not known. It has been suggested that prion strains with unique self-replicating and neurotoxic properties emerge spontaneously in individuals carrying PrP mutations, dictating the phenotypic expression of disease. We generated transgenic mice expressing the FFI mutation, and found that they developed a fatal neurological illness highly reminiscent of FFI, and different from those of similarly generated mice modeling genetic CJD and GSS. Thus transgenic mice recapitulate the phenotypic differences seen in humans. The mutant PrPs expressed in these mice are misfolded but unable to self-replicate. They accumulate in different compartments of the neuronal secretory pathway, impairing the membrane delivery of ion channels essential for neuronal function. Our results indicate that conversion of mutant PrP into an infectious isoform is not required for pathogenesis, and suggest that the phenotypic variability may be due to different effects of mutant PrP on intracellular transport. PMID:26864450

  1. Prion Disease Induces Alzheimer Disease-Like Neuropathologic Changes

    PubMed Central

    Tousseyn, Thomas; Bajsarowicz, Krystyna; Sánchez, Henry; Gheyara, Ania; Oehler, Abby; Geschwind, Michael; DeArmond, Bernadette; DeArmond, Stephen J.

    2016-01-01

    We examined the brains of 266 patients with prion diseases (PrionD) and found that 46 (17%) had Alzheimer disease (AD)-like changes. To explore potential mechanistic links between PrionD and AD, we exposed human brain aggregates (Hu BrnAggs) to brain homogenate from a patient with sporadic Creutzfeldt-Jakob disease (CJD) and found that the neurons in the Hu BrnAggs produced many β-amyloid (β42) inclusions, whereas uninfected, control-exposed Hu BrnAggs did not. Western blots of 20-pooled CJD-infected BrnAggs verified higher Aβ42 levels than controls. We next examined the CA1 region of the hippocampus from 14 patients with PrionD and found that 5 patients had low levels of scrapie-associated prion protein (PrPSc), many Aβ42 intraneuronal inclusions, low APOE-4, and no significant nerve cell loss. Seven patients had high levels of PrPSc, low Aβ42, high APOE-4 and 40% nerve cell loss, suggesting that APOE-4 and PrPSc together cause neuron loss in PrionD. There were also increased levels of hyperphosphorylated tau protein (Hτ) and Hτ-positive neuropil threads and neuron bodies in both PrionD and AD groups. The brains of 6 age-matched control patients without dementia did not contain Aβ42 deposits; however, there were rare Hτ-positive threads in 5 controls and 2 controls had a few Hτ-positive nerve cell bodies. We conclude that PrionD may trigger biochemical changes similar to AD and suggest that PrionD are diseases of PrPSc, Aβ42, APOE-4 and abnormal tau. PMID:26226132

  2. Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease

    PubMed Central

    Sassi, Celeste; Guerreiro, Rita; Gibbs, Raphael; Ding, Jinhui; Lupton, Michelle K.; Troakes, Claire; Al-Sarraj, Safa; Niblock, Michael; Gallo, Jean-Marc; Adnan, Jihad; Killick, Richard; Brown, Kristelle S.; Medway, Christopher; Lord, Jenny; Turton, James; Bras, Jose; Morgan, Kevin; Powell, John F.; Singleton, Andrew; Hardy, John

    2014-01-01

    The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raise the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias. PMID:25104557

  3. Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease.

    PubMed

    Sassi, Celeste; Guerreiro, Rita; Gibbs, Raphael; Ding, Jinhui; Lupton, Michelle K; Troakes, Claire; Lunnon, Katie; Al-Sarraj, Safa; Brown, Kristelle S; Medway, Chirstopher; Lord, Jenny; Turton, James; Mann, David; Snowden, Julie; Neary, David; Harris, Jeniffer; Bras, Jose; Morgan, Kevin; Powell, John F; Singleton, Andrew; Hardy, John

    2014-10-01

    Early-onset Alzheimer's disease (EOAD) represents 1%-2% of the Alzheimer's disease (AD) cases, and it is generally characterized by a positive family history and a rapidly progressive symptomatology. Rare coding and fully penetrant variants in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the only causative mutations reported for autosomal dominant AD. Thus, in this study we used exome sequencing data to rapidly screen rare coding variability in APP, PSEN1, and PSEN2, in a British cohort composed of 47 unrelated EOAD cases and 179 elderly controls, neuropathologically proven. We report 2 novel and likely pathogenic variants in PSEN1 (p.L166V and p.S230R). A comprehensive catalog of rare pathogenic variants in the AD Mendelian genes is pivotal for a premortem diagnosis of autosomal dominant EOAD and for the differential diagnosis with other early onset dementias such as frontotemporal dementia (FTD) and Creutzfeldt-Jakob disease (CJD).

  4. One gene, two diseases and three conformations: molecular dynamics simulations of mutants of human prion protein at room temperature and elevated temperatures.

    PubMed

    Shamsir, Mohd S; Dalby, Andrew R

    2005-05-01

    Fatal familial insomnia (FFI) and Creutzfeldt-Jakob disease (CJD) are associated to the same mutation at codon 178 but differentiate into clinicopathologically distinct diseases determined by this mutation and a naturally occurring methionine-valine polymorphism at codon 129 of the prion protein gene. It has been suggested that the clinical and pathological difference between FFI and CJD is caused by different conformations of the prion protein. Using molecular dynamics (MD), we investigated the effect of the mutation at codon 178 and the polymorphism at codon 129 on prion protein dynamics and conformation at normal and elevated temperatures. Four model structures were examined with a focus on their dynamics and conformational changes. The results showed differences in stability and dynamics between polymorphic variants. Methionine variants demonstrated a higher stability than valine variants. Elongation of existing beta-sheets and formation of new beta-sheets was found to occur more readily in valine polymorphic variants. We also discovered the inhibitory effect of proline residue on existing beta-sheet elongation.

  5. Human prion diseases: surgical lessons learned from iatrogenic prion transmission

    PubMed Central

    Bonda, David J.; Manjila, Sunil; Mehndiratta, Prachi; Khan, Fahd; Miller, Benjamin R.; Onwuzulike, Kaine; Puoti, Gianfranco; Cohen, Mark L.; Schonberger, Lawrence B.; Cali, Ignazio

    2016-01-01

    The human prion diseases, or transmissible spongiform encephalopathies, have captivated our imaginations since their discovery in the Fore linguistic group in Papua New Guinea in the 1950s. The mysterious and poorly understood “infectious protein” has become somewhat of a household name in many regions across the globe. From bovine spongiform encephalopathy (BSE), commonly identified as mad cow disease, to endocannibalism, media outlets have capitalized on these devastatingly fatal neurological conditions. Interestingly, since their discovery, there have been more than 492 incidents of iatrogenic transmission of prion diseases, largely resulting from prion-contaminated growth hormone and dura mater grafts. Although fewer than 9 cases of probable iatrogenic neurosurgical cases of Creutzfeldt-Jakob disease (CJD) have been reported worldwide, the likelihood of some missed cases and the potential for prion transmission by neurosurgery create considerable concern. Laboratory studies indicate that standard decontamination and sterilization procedures may be insufficient to completely remove infectivity from prion-contaminated instruments. In this unfortunate event, the instruments may transmit the prion disease to others. Much caution therefore should be taken in the absence of strong evidence against the presence of a prion disease in a neurosurgical patient. While the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have devised risk assessment and decontamination protocols for the prevention of iatrogenic transmission of the prion diseases, incidents of possible exposure to prions have unfortunately occurred in the United States. In this article, the authors outline the historical discoveries that led from kuru to the identification and isolation of the pathological prion proteins in addition to providing a brief description of human prion diseases and iatrogenic forms of CJD, a brief history of prion disease nosocomial

  6. Treatment of Prion Disease with Heterologous Prion Proteins

    PubMed Central

    Skinner, Pamela J.; Kim, Hyeon O.; Bryant, Damani; Kinzel, Nikilyn J.; Reilly, Cavan; Priola, Suzette A.; Ward, Anne E.; Goodman, Patricia A.; Olson, Katherine; Seelig, Davis M.

    2015-01-01

    Prion diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep are fatal neurodegenerative diseases for which there is no effective treatment. The pathology of these diseases involves the conversion of a protease sensitive form of the cellular prion protein (PrPC) into a protease resistant infectious form (PrPsc or PrPres). Both in vitro (cell culture and cell free conversion assays) and in vivo (animal) studies have demonstrated the strong dependence of this conversion process on protein sequence homology between the initial prion inoculum and the host’s own cellular prion protein. The presence of non-homologous (heterologous) proteins is often inhibitory to this conversion process. We hypothesize that the presence of heterologous prion proteins from one species might therefore constitute an effective treatment for prion disease in another species. To test this hypothesis, we infected mice intracerebrally with murine adapted RML-Chandler scrapie and treated them with heterologous prion protein (purified bacterially expressed recombinant hamster prion protein) or vehicle alone. Treated animals demonstrated reduced disease associated pathology, decreased accumulation of protease-resistant disease-associated prion protein, with delayed onset of clinical symptoms and motor deficits. This was concomitant with significantly increased survival times relative to mock-treated animals. These results provide proof of principle that recombinant hamster prion proteins can effectively and safely inhibit prion disease in mice, and suggest that hamster or other non-human prion proteins may be a viable treatment for prion diseases in humans. PMID:26134409

  7. Less protease-resistant PrP in a patient with sporadic CJD treated with intraventricular pentosan polysulphate.

    PubMed

    Terada, T; Tsuboi, Y; Obi, T; Doh-ura, K; Murayama, S; Kitamoto, T; Yamada, T; Mizoguchi, K

    2010-02-01

    Treatment with intraventricular pentosan polysulphate (PPS) might be beneficial in patients with Creutzfeldt-Jakob disease. We report a 68-year-old woman with sporadic Creutzfeldt-Jakob disease who received continuous intraventricular PPS infusion (1-120 microg/kg/day) for 17 months starting 10 months after the onset of clinical symptoms. Treatment with PPS was well tolerated but was associated with a minor, transient intraventricular hemorrhage and a non-progressive collection of subdural fluid. The patient's overall survival time was well above the mean time expected for the illness but still within the normal range. Post-mortem examination revealed that the level of abnormal protease-resistant prion protein in the brain was markedly decreased compared with levels in brains without PPS treatment. These findings suggest that intraventricular PPS infusion might modify the accumulation of abnormal prion proteins in the brains of patients with sporadic Creutzfeldt-Jakob disease.

  8. Clinical Issues-May 2016.

    PubMed

    Van Wicklin, Sharon A

    2016-05-01

    Variations in documenting surgical wound classification Key words: surgical wound classification, clean, clean-contaminated, contaminated, dirty. Wearing long-sleeved jackets while preparing and packaging items for sterilization Key words: long-sleeved jackets, organic material, sterile processing. Endoscopic transmission of prions Key words: prions, high-risk tissue, low-risk tissue, Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD). Wearing gloves when handling flexible endoscopes Key words: gloves, low-protein, powder-free, natural rubber latex gloves, latex-free gloves.

  9. Genetic Characterization of Movement Disorders and Dementias

    ClinicalTrials.gov

    2017-09-28

    Ataxia; Dystonia; Parkinson's Disease; Amyotrophic Lateral Sclerosis; Corticobasal Degeneration; Multiple System Atrophy; Alzheimer's Disease; Lewy Body Dementia; Parkinson Disease-Dementia; Dentatorubral-pallidoluysian Atrophy; Creutzfeldt-Jakob Disease and Fatal Familial Insomnia; Fragile X-associated Tremor/Ataxia Syndrome; Krabbe's Disease; Niemann-Pick Disease, Type C; Neuronal Ceroid Lipofuscinosis

  10. Olfactory Receptors in Non-Chemosensory Organs: The Nervous System in Health and Disease

    PubMed Central

    Ferrer, Isidro; Garcia-Esparcia, Paula; Carmona, Margarita; Carro, Eva; Aronica, Eleonora; Kovacs, Gabor G.; Grison, Alice; Gustincich, Stefano

    2016-01-01

    Olfactory receptors (ORs) and down-stream functional signaling molecules adenylyl cyclase 3 (AC3), olfactory G protein α subunit (Gαolf), OR transporters receptor transporter proteins 1 and 2 (RTP1 and RTP2), receptor expression enhancing protein 1 (REEP1), and UDP-glucuronosyltransferases (UGTs) are expressed in neurons of the human and murine central nervous system (CNS). In vitro studies have shown that these receptors react to external stimuli and therefore are equipped to be functional. However, ORs are not directly related to the detection of odors. Several molecules delivered from the blood, cerebrospinal fluid, neighboring local neurons and glial cells, distant cells through the extracellular space, and the cells’ own self-regulating internal homeostasis can be postulated as possible ligands. Moreover, a single neuron outside the olfactory epithelium expresses more than one receptor, and the mechanism of transcriptional regulation may be different in olfactory epithelia and brain neurons. OR gene expression is altered in several neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2 with disease-, region- and subtype-specific patterns. Altered gene expression is also observed in the prefrontal cortex in schizophrenia with a major but not total influence of chlorpromazine treatment. Preliminary parallel observations have also shown the presence of taste receptors (TASRs), mainly of the bitter taste family, in the mammalian brain, whose function is not related to taste. TASRs in brain are also abnormally regulated in neurodegenerative diseases. These seminal observations point to the need for further studies on ORs and TASRs chemoreceptors in the mammalian brain. PMID:27458372

  11. The cognitive profile of prion disease: a prospective clinical and imaging study

    PubMed Central

    Caine, Diana; Tinelli, Renata J; Hyare, Harpreet; De Vita, Enrico; Lowe, Jessica; Lukic, Ana; Thompson, Andrew; Porter, Marie-Claire; Cipolotti, Lisa; Rudge, Peter; Collinge, John; Mead, Simon

    2015-01-01

    Objectives Prion diseases are dementing illnesses with poorly defined neuropsychological features. This is probably because the most common form, sporadic Creutzfeldt-Jakob disease, is often rapidly progressive with pervasive cognitive decline making detailed neuropsychological investigation difficult. This study, which includes patients with inherited, acquired (iatrogenic and variant) and sporadic forms of the disease, is the only large-scale neuropsychological investigation of this patient group ever undertaken and aimed to define a neuropsychological profile of human prion diseases. Methods A tailored short cognitive examination of all of the patients (n = 81), with detailed neuropsychological testing in a subset with mild disease (n = 30) and correlation with demographic, clinical, genetic (PRNP mutation and polymorphic codon 129 genotype), and other variables (MRI brain signal change in cortex, basal ganglia or thalamus; quantitative research imaging, cerebrospinal fluid 14-3-3 protein). Results Comparison with healthy controls showed patients to be impaired on all tasks. Principal components analysis showed a major axis of fronto-parietal dysfunction that accounted for approximately half of the variance observed. This correlated strongly with volume reduction in frontal and parietal gray matter on MRI. Examination of individual patients' performances confirmed early impairment on this axis, suggesting characteristic cognitive features in mild disease: prominent executive impairment, parietal dysfunction, a largely expressive dysphasia, with reduced motor speed. Interpretation Taken together with typical neurological features, these results complete a profile that should improve differential diagnosis in a clinical setting. We propose a tailored neuropsychological battery for early recognition of clinical onset of symptoms with potential for use in clinical trials involving at-risk individuals. PMID:26000326

  12. Evidence of subclinical prion disease in aged mice following exposure to bovine spongiform encephalopathy.

    PubMed

    Brown, Karen L; Mabbott, Neil A

    2014-01-01

    The occurrence of variant Creutzfeldt-Jakob (vCJD) disease in humans was almost certainly the result of consumption of food contaminated with bovine spongiform encephalopathy (BSE) prions. Despite probable widespread exposure of the UK population to BSE-contaminated food in the 1980s, vCJD has been identified predominantly in young individuals, and there have been fewer cases of clinical disease than anticipated. The reasons for this are uncertain. Following peripheral exposure, many prions replicate within the lymphoid tissues before infecting the central nervous system. We have shown that the effects of host age on the microarchitecture of the spleen significantly impair susceptibility to mouse-adapted prions after peripheral exposure. The transmission of prions between different mammalian species is considered to be limited by the 'species barrier', which is dependent on several factors, including an intact immune system. Thus, cross-species prion transmission may be much less efficient in aged individuals. To test this hypothesis, we compared prion pathogenesis in groups of young (6-8 weeks old) and aged (600 days old) mice injected with primary BSE brain homogenate. We showed that prion pathogenesis was impaired dramatically in aged mice when compared with young animals. Whereas most young mice succumbed to clinical prion disease, all aged mice failed to develop clinical disease during their lifespans. However, the demonstration that prion accumulation was detected in the lymphoid tissues of some aged mice after injection with primary BSE brain homogenate, in the absence of clinical signs of prion disease, has important implications for human health.

  13. Detecting and quantifying prions: Mass spectrometry-based approaches

    USDA-ARS?s Scientific Manuscript database

    Prions are novel pathogens that cause a set of rare fatal neurological diseases know as transmissible spongiform encephalopathies. Examples of these diseases include Creutzfeldt-Jakob disease, scrapie and chronic wasting disease. Prions are able to recruit a normal cellular prion protein and convert...

  14. 21 CFR 1271.75 - How do I screen a donor?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... method that ensures freedom from contamination of the cells or tissue by infectious disease organisms...) Risk factors for, and clinical evidence of, relevant communicable disease agents and diseases... transmissible spongiform encephalopathy, including Creutzfeldt-Jakob disease; (v) Treponema pallidum; and (2...

  15. 21 CFR 1271.75 - How do I screen a donor?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... method that ensures freedom from contamination of the cells or tissue by infectious disease organisms...) Risk factors for, and clinical evidence of, relevant communicable disease agents and diseases... transmissible spongiform encephalopathy, including Creutzfeldt-Jakob disease; (v) Treponema pallidum; and (2...

  16. 21 CFR 1271.75 - How do I screen a donor?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... method that ensures freedom from contamination of the cells or tissue by infectious disease organisms...) Risk factors for, and clinical evidence of, relevant communicable disease agents and diseases... transmissible spongiform encephalopathy, including Creutzfeldt-Jakob disease; (v) Treponema pallidum; and (2...

  17. A low molecular-weight ferroxidase is increased in the CSF of sCJD cases: CSF ferroxidase and transferrin as diagnostic biomarkers for sCJD

    USDA-ARS?s Scientific Manuscript database

    Imbalance of brain iron homeostasis is a common feature of neurodegenerative conditions that include sporadic Creutzfeldt-Jakob disease (sCJD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease, among others. However, the mechanisms underlying this change are unclear. In s...

  18. Retinal function and morphology are altered in cattle infected with the prion disease transmissible mink encephalopathy.

    PubMed

    Smith, J D; Greenlee, J J; Hamir, A N; Richt, J A; Greenlee, M H West

    2009-09-01

    Transmissible spongiform encephalopathies (TSEs) are a group of diseases that result in progressive and invariably fatal neurologic disease in both animals and humans. TSEs are characterized by the accumulation of an abnormal protease-resistant form of the prion protein in the central nervous system. Transmission of infectious TSEs is believed to occur via ingestion of prion protein-contaminated material. This material is also involved in the transmission of bovine spongiform encephalopathy ("mad cow disease") to humans, which resulted in the variant form of Creutzfeldt-Jakob disease. Abnormal prion protein has been reported in the retina of TSE-affected cattle, but despite these observations, the specific effect of abnormal prion protein on retinal morphology and function has not been assessed. The objective of this study was to identify and characterize potential functional and morphologic abnormalities in the retinas of cattle infected with a bovine-adapted isolate of transmissible mink encephalopathy. We used electroretinography and immunohistochemistry to examine retinas from 10 noninoculated and 5 transmissible mink encephalopathy-inoculated adult Holstein steers. Here we show altered retinal function, as evidenced by prolonged implicit time of the electroretinogram b-wave, in transmissible mink encephalopathy-infected cattle before the onset of clinical illness. We also demonstrate disruption of rod bipolar cell synaptic terminals, indicated by decreased immunoreactivity for the alpha isoform of protein kinase C and vesicular glutamate transporter 1, and activation of Müller glia, as evidenced by increased glial fibrillary acidic protein and glutamine synthetase expression, in the retinas of these cattle at the time of euthanasia due to clinical deterioration. This is the first study to identify both functional and morphologic alterations in the retinas of TSE-infected cattle. Our results support future efforts to focus on the retina for the development of

  19. Iron in neurodegenerative disorders of protein misfolding: a case of prion disorders and Parkinson's disease.

    PubMed

    Singh, Neena; Haldar, Swati; Tripathi, Ajai K; McElwee, Matthew K; Horback, Katharine; Beserra, Amber

    2014-07-20

    Intracellular and extracellular aggregation of a specific protein or protein fragments is the principal pathological event in several neurodegenerative conditions. We describe two such conditions: sporadic Creutzfeldt-Jakob disease (sCJD), a rare but potentially infectious and invariably fatal human prion disorder, and Parkinson's disease (PD), a common neurodegenerative condition second only to Alzheimer's disease in prevalence. In sCJD, a cell surface glycoprotein known as the prion protein (PrP(C)) undergoes a conformational change to PrP-scrapie, a pathogenic and infectious isoform that accumulates in the brain parenchyma as insoluble aggregates. In PD, α-synuclein, a cytosolic protein, forms insoluble aggregates that accumulate in neurons of the substantia nigra and cause neurotoxicity. Although distinct processes are involved in the pathogenesis of sCJD and PD, both share brain iron dyshomeostasis as a common associated feature that is reflected in the cerebrospinal fluid in a disease-specific manner. Since PrP(C) and α-synuclein play a significant role in maintaining cellular iron homeostasis, it is important to understand whether the aggregation of these proteins and iron dyshomeostasis are causally related. Here, we discuss recent information on the normal function of PrP(C) and α-synuclein in cellular iron metabolism and the cellular and biochemical processes that contribute to iron imbalance in sCJD and PD. Improved understanding of the relationship between brain iron imbalance and protein aggregation is likely to help in the development of therapeutic strategies that can restore brain iron homeostasis and mitigate neurotoxicity.

  20. A naturally occurring variant of the human prion protein completely prevents prion disease.

    PubMed

    Asante, Emmanuel A; Smidak, Michelle; Grimshaw, Andrew; Houghton, Richard; Tomlinson, Andrew; Jeelani, Asif; Jakubcova, Tatiana; Hamdan, Shyma; Richard-Londt, Angela; Linehan, Jacqueline M; Brandner, Sebastian; Alpers, Michael; Whitfield, Jerome; Mead, Simon; Wadsworth, Jonathan D F; Collinge, John

    2015-06-25

    Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.

  1. Detection of PrP(Sc) in peripheral tissues of clinically affected cattle after oral challenge with bovine spongiform encephalopathy

    USDA-ARS?s Scientific Manuscript database

    Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative prion disease that affects cattle and can be transmitted to human beings as new variant Creutzfeldt-Jakob disease (vCJD). A protease-resistant, disease-associated isoform of the prion protein (PrP**Sc) accumulates in the central ner...

  2. Ian McEwan--novels about neurological and psychiatric patients.

    PubMed

    Rot, Uros

    2008-01-01

    Ian McEwan, a respected contemporary British writer, sometimes uses neurological and psychiatric patients as main characters of his stories. In his recent novels one can find beautiful descriptions of patients with Huntington's disease, variant Creutzfeldt-Jakob disease, de Clerambault syndrome and also details about some neurosurgical procedures. (c) 2008 S. Karger AG, Basel.

  3. Mass Spectrometry of Prions: Approaches to Conformational Distinction

    USDA-ARS?s Scientific Manuscript database

    Prions are the agents that cause a set of fatal neurological diseases that include Creutzfeldt-Jakob disease. Prions are composed solely of protein. Unlike viral, bacterial, or fungal pathogens, the information necessary to propagate the infection is contained in the conformation of the prion isofor...

  4. Kuru in the 21st century--an acquired human prion disease with very long incubation periods.

    PubMed

    Collinge, John; Whitfield, Jerome; McKintosh, Edward; Beck, John; Mead, Simon; Thomas, Dafydd J; Alpers, Michael P

    2006-06-24

    Kuru provides the principal experience of epidemic human prion disease. Its incidence has steadily fallen after the abrupt cessation of its route of transmission (endocannibalism) in Papua New Guinea in the 1950s. The onset of variant Creutzfeldt-Jakob disease (vCJD), and the unknown prevalence of infection after the extensive dietary exposure to bovine spongiform encephalopathy (BSE) prions in the UK, has led to renewed interest in kuru. We investigated possible incubation periods, pathogenesis, and genetic susceptibility factors in kuru patients in Papua New Guinea. We strengthened active kuru surveillance in 1996 with an expanded field team to investigate all suspected patients. Detailed histories of residence and exposure to mortuary feasts were obtained together with serial neurological examination, if possible. We identified 11 patients with kuru from July, 1996, to June, 2004, all living in the South Fore. All patients were born before the cessation of cannibalism in the late 1950s. The minimum estimated incubation periods ranged from 34 to 41 years. However, likely incubation periods in men ranged from 39 to 56 years and could have been up to 7 years longer. PRNP analysis showed that most patients with kuru were heterozygous at polymorphic codon 129, a genotype associated with extended incubation periods and resistance to prion disease. Incubation periods of infection with human prions can exceed 50 years. In human infection with BSE prions, species-barrier effects, which are characteristic of cross-species transmission, would be expected to further increase the mean and range of incubation periods, compared with recycling of prions within species. These data should inform attempts to model variant CJD epidemiology.

  5. Protease-resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion.

    PubMed

    Honda, Hiroyuki; Sasaki, Kensuke; Minaki, Haruhiko; Masui, Kenta; Suzuki, Satoshi O; Doh-Ura, Katsumi; Iwaki, Toru

    2012-04-01

    Intraventricular infusion of pentosan polysulfate (PPS) as a treatment for various human prion diseases has been applied in Japan. To evaluate the influence of PPS treatment we performed pathological examination and biochemical analyses of PrP molecules in autopsied brains treated with PPS (one case of sporadic Creutzfeldt-Jakob disease (sCJD, case 1), two cases of dura mater graft-associated CJD (dCJD, cases 2 and 4), and one case of Gerstmann-Sträussler-Scheinker disease (GSS, case 3). Six cases of sCJD without PPS treatment were examined for comparison. Protease-resistant PrP (PrP(res) ) in the frontal lobe was evaluated by Western blotting after proteinase K digestion. Further, the degree of polymerization of PrP molecules was examined by the size-exclusion gel chromatography assay. PPS infusions were started 3-10 months after disease onset, but the treatment did not achieve any clinical improvements. Postmortem examinations of the treated cases revealed symmetrical brain lesions, including neuronal loss, spongiform change and gliosis. Noteworthy was GFAP in the cortical astrocytes reduced in all treated cases despite astrogliosis. Immunohistochemistry for PrP revealed abnormal synaptic deposits in all treated cases and further plaque-type PrP deposition in case 3 of GSS and case 4 of dCJD. Western blotting showed relatively low ratios of PrP(res) in case 2 of dCJD and case 3 of GSS, while in the treated sCJD (case 1), the ratio of PrP(res) was comparable with untreated cases. The indices of oligomeric PrP were reduced in one sCJD (case 1) and one dCJD (case 2). Although intraventricular PPS infusion might modify the accumulation of PrP oligomers in the brains of patients with prion diseases, the therapeutic effects are still uncertain. © 2011 Japanese Society of Neuropathology.

  6. Transmission of scrapie prions to primate after an extended silent incubation period.

    PubMed

    Comoy, Emmanuel E; Mikol, Jacqueline; Luccantoni-Freire, Sophie; Correia, Evelyne; Lescoutra-Etchegaray, Nathalie; Durand, Valérie; Dehen, Capucine; Andreoletti, Olivier; Casalone, Cristina; Richt, Juergen A; Greenlee, Justin J; Baron, Thierry; Benestad, Sylvie L; Brown, Paul; Deslys, Jean-Philippe

    2015-06-30

    Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly relevant model for human prion diseases, after a 10-year silent incubation period, with features similar to those reported for human cases of sporadic CJD. Scrapie is thus actually transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE. Long-term experimental transmission studies are necessary to better assess the zoonotic potential of other prion diseases with high prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98 scrapie.

  7. Transmission of scrapie prions to primate after an extended silent incubation period

    PubMed Central

    Comoy, Emmanuel E.; Mikol, Jacqueline; Luccantoni-Freire, Sophie; Correia, Evelyne; Lescoutra-Etchegaray, Nathalie; Durand, Valérie; Dehen, Capucine; Andreoletti, Olivier; Casalone, Cristina; Richt, Juergen A.; Greenlee, Justin J.; Baron, Thierry; Benestad, Sylvie L.; Brown, Paul; Deslys, Jean-Philippe

    2015-01-01

    Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly relevant model for human prion diseases, after a 10-year silent incubation period, with features similar to those reported for human cases of sporadic CJD. Scrapie is thus actually transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE. Long-term experimental transmission studies are necessary to better assess the zoonotic potential of other prion diseases with high prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98 scrapie. PMID:26123044

  8. 75 FR 55803 - Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-14

    ... the variant Creutzfeldt-Jakob disease (vCJD) agent in U.S.-licensed plasma-derived Factor VIII and (2) labeling of blood and blood components and plasma-derived products, including plasma-derived albumin and products containing plasma-derived albumin, to address the possible risk of transmission of vCJD. On...

  9. Typical and atypical cases of bovine spongiform encephalopathy

    USDA-ARS?s Scientific Manuscript database

    Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy of cattle, first detected in 1986 in the United Kingdom and subsequently in other countries. It is the most likely cause of variant Creutzfeldt-Jakob disease (vCJD) in humans, but the origin of BSE has not been eluci...

  10. Fluorescence of tissues fluororophores such as lipofuscin as a possible basis for the detection of CNS tissues on bovine carcasses

    USDA-ARS?s Scientific Manuscript database

    Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative transmissible spongiform encephalopathy (TSE) which is thought to cause variant of Creutzfeldt-Jakob disease (vCJD) in humans. It is believed that humans contract vCJD by consumption of meat contaminated with bovine tissue containi...

  11. Variations in neurodegenerative disease across the UK: findings from the national study of Progressive Intellectual and Neurological Deterioration (PIND)

    PubMed Central

    Devereux, G; Stellitano, L; Verity, C; Nicoll, A; Will, R; Rogers, P

    2004-01-01

    Aims: To identify any UK children with variant Creutzfeldt-Jakob disease (vCJD) and obtain information about the causes of progressive intellectual and neurological deterioration (PIND) and the geographical distribution of cases. Methods: The PIND Study uses the monthly surveillance card that is sent to all UK paediatricians by the British Paediatric Surveillance Unit. Case details are obtained from the reporting paediatricians by telephone interview, site visit, or self completion of a questionnaire. A paediatric neurology expert group then classifies the anonymised cases. The Communicable Disease Surveillance Centre (CDSC) provides mapping support. Results: After five years and five months of surveillance, 1400 children had been reported. In the UK the majority of PIND cases had a confirmed diagnosis (comprising 99 different conditions); 505 "no cases" and 97 "outstanding" cases were excluded. A total of 798 PIND cases were included as follows: 577 with a confirmed underlying diagnosis; six with definite or probable vCJD, 51 who had undiagnosed PIND but were not thought to have vCJD, and 164 cases who were still under investigation. In some districts there were unexpectedly high numbers of PIND cases with a heterogeneous mixture of underlying diagnoses. In the five districts with the largest numbers of resident cases the majority not only came from a particular ethnic group but also had high reported rates of consanguinity. Conclusions: In districts with large numbers of PIND cases there are major resource implications. These children and their families have complex problems and they need access to diagnostic facilities and appropriate service provision. PMID:14709491

  12. Fundamental immunological problems associated with "transmissible spongiform encephalopathies".

    PubMed

    Ebringer, Alan; Rashid, Taha; Wilson, Clyde

    2015-02-01

    "Bovine spongiform encephalopathy", "scrapie", as well as Creutzfeldt-Jakob disease and kuru belong to a group of related neurological conditions termed "transmissible spongiform encephalopathies". These diseases are based on the LD50 measurement whereby saline brain homogenates are injected into experimental animals and when 50% of them develop symptoms, this is considered as transmission of the disease, but the gold standard for diagnosis is autopsy examination. However, an untenable assumption is being made in that saline brain homogenates do not cause tissue damage but it is known since the time of Pasteur, that they give rise to "post-rabies vaccination allergic encephalomyelitis". This is the fundamental flaw in the diagnosis of these diseases. A way forward, however, is to examine infectious agents, such as Acinetobacter which show molecular mimicry with myelin and elevated levels of antibodies to this microbe are found in multiple sclerosis patients and animals affected by "bovine spongiform encephalopathy".

  13. Quantitative measurement of the efficacy of protein removal by cleaning formulations; comparative evaluation of prion-directed cleaning chemistries.

    PubMed

    Ungurs, M; Hesp, J R; Poolman, T; McLuckie, G; O'Brien, S; Murdoch, H; Wells, P; Raven, N D H; Walker, J T; Sutton, J M

    2010-02-01

    The stability of the infectious agent causing variant Creutzfeldt-Jakob disease (vCJD) has highlighted the importance of cleaning surgical instruments for controlling potential spread of iatrogenic CJD. In this study, thermostable adenylate kinases (tAKs) in test soil were coated on to stainless steel and these surrogate agents used to evaluate the efficacy of a range of cleaning chemistries in a bench-top washer disinfector (btWD), or as a pre-soak either with or without subsequent treatment by btWD. Two tAKs were tested initially for ease of removal, the most persistent being Sulfolobus acidocaldarius-derived tAK which was used for evaluating the cleaning chemistries. Conventional chemistries were generally more effective when used in a btWD than as pre-soaks. Cleaning efficacy improved when pre-soaks were followed by treatment with intermediate performing enzymes, demonstrating greater than additive effect on residual tAK activity. Three of the four prion-directed chemistries reduced residual tAK activity to below the limit of quantification (LoQ) by more than 4.8 log(10); <175pg tAK remaining as a pre-soak alone. A conventional alkaline cleaning product also reduced residual tAK activity to below the LoQ but only when used in a btWD. tAK soil dried on to the device was removed less efficiently than tAK soil still moist on the device, with a 320-fold and 28-fold increase in residual tAK activity for pre-soak and btWD, respectively. The study demonstrated the potential for a tAK indicator to describe the effectiveness of protein removal using different chemistries or treatment processes.

  14. Cling film as a barrier against CJD in corneal contact A-scan ultrasonography.

    PubMed

    Rani, Asha; Dunne, Mark C M; Barnes, Derek A

    2003-01-01

    To determine the validity of covering a corneal contact transducer probe with cling film as protection against the transmission of Creutzfeldt-Jakob disease (CJD). The anterior chamber depth, lens thickness and vitreous chamber depth of the right eyes of 10 subjects was recorded, under cycloplegia, with and without cling film covering over the transducer probe of a Storz Omega Compu-scan Biometric Ruler. Measurements were repeated on two occasions. Cling film covering did not influence bias or repeatability. Although the 95% limits of agreement between measurements made with and without cling film covering tended to exceed the intrasessional repeatability, they did not exceed the intersessional repeatability of measurements taken without cling film. The results support the use of cling film as a disposable covering for corneal contact A-scan ultrasonography to avoid the risk of spreading CJD from one subject to another.

  15. Highly sensitive rapid fluorescence detection of protein residues on surgical instruments

    NASA Astrophysics Data System (ADS)

    Kovalev, Valeri I.; Barton, James S.; Richardson, Patricia R.; Jones, Anita C.

    2006-02-01

    There is a risk of contamination of surgical instruments by nfectious protein residues, in particular, prions which are the agents for Creutzfeldt-Jakob Disease in humans. They are exceptionally resistant to conventional sterilization, therefore it is important to detect their presence as contaminants so that alternative cleaning procedures can be applied. We describe the development of an optimized detection system for fluorescently labelled protein, suitable for in-hospital use. We show that under optimum conditions the technique can detect ~100 zeptomoles/mm2 with an area scan speed of ~20 cm2/s and for using the system to detect other agents of biomedical interest. A theoretical analysis and experimental measurements will be discussed.

  16. Elucidation of endemic neurodegenerative diseases--a commentary.

    PubMed

    Nishida, Yuzo

    2003-01-01

    Recent investigations of scrapie, Creutzfeldt-Jakob disease (CJD), and chronic wasting disease (CWD) clusters in Iceland, Slovakia and Colorado, respectively, have indicated that the soil in these regions is low in copper and higher in manganese, and it has been well-known that patients of ALS or Parkinson's disease were collectively found in the New Guinea and Papua islands, where the subterranean water (drinking water) contains much Al3+ and Mn2+ ions. Above facts suggest that these neurodegenerative diseases are closely related with the function of a metal ion. We have investigated the chemical functions of the metal ions in detail and established the unique mechanism of the oxygen activation by the transition metal ions such as iron and copper, and pointed out the notable difference in the mechanism among iron, aluminum and manganese ions. Based on these results, it has become apparent that the incorporation of Al(III) or Mn(II) in the cells induces the "iron-overload syndrome", which is mainly due to the difference in an oxygen activation mechanism between the iron ion and Al(III) or the Mn(II) ion. This syndrome highly promotes formation of hydrogen peroxide, and hydrogen peroxide thus produced can be a main factor to cause serious damages to DNA and proteins (oxidative stress), yielding a copper(II)- or manganese(II)-peptide complex and its peroxide adduct, which are the serious agents to induce the structural changes from the normal prion protein (PrP(c)) to abnormal disease-causing isoforms, PrP(Sc), or the formation of PrP 27-30 (abnormal cleavage at site 90 of the prion protein). It seems reasonable to consider that the essential origin for the transmissible spongiform encephalopathies (TSEs) should be the incorporation and accumulation of Al(III) and Mn(II) ions in the cells, and the sudden and explosive increase of scrapie and bovine spongiform encephalopathy (BSE) in the last decade may be partially due to "acid rain", because the acid rain makes Al

  17. [Measurement of disease severity in dermatology].

    PubMed

    Deckert, S; Apfelbacher, C; Schmitt, J

    2015-09-01

    In order to determine the appropriate therapy for dermatological diseases, numerous measurement instruments are available to measure disease severity. Due to the lack of laboratory parameters for some dermatological diseases to objectify the disease severity (e.g., atopic dermatitis, psoriasis), questionnaires are used. Laboratory as well as questionnaire-based measurements should be reliable, valid, and sensitive to change. In addition, measurement instruments should be feasible. Classifications of disease severity which are based on inadequate measurement properties result in incorrect clinical decisions and limit evidence-based healthcare. Therefore, systematically developed and evidence-based recommendations for the use of individual measurement instruments should be taken into consideration.

  18. Mononucleated Blood Cell Populations Display Different Abilities To Transmit Prion Disease by the Transfusion Route

    PubMed Central

    Douet, Jean-Yves; Lacroux, Caroline; Litaise, Claire; Lugan, Séverine; Corbière, Fabien; Arnold, Mark; Simmons, Hugh; Aron, Naima; Costes, Pierrette; Tillier, Cécile; Cassard, Hervé

    2016-01-01

    ABSTRACT Previous experiments carried out in a sheep scrapie model demonstrated that the transfusion of 200 μl of prion-infected whole blood has an apparent 100% efficacy for disease transmission. These experiments also indicated that, despite the apparent low infectious titer, the intravenous administration of white blood cells (WBC) resulted in efficient disease transmission. In the study presented here, using the same transmissible spongiform encephalopathy (TSE) animal model, our aim was to determine the minimal number of white blood cells and the specific abilities of mononucleated cell populations to transmit scrapie by the transfusion route. Our results confirmed that the transfusion of 100 μl, but not 10 μl, of fresh whole blood collected in asymptomatic scrapie-infected donor sheep can transmit the disease. The data also show that the intravenous administration of 105 WBCs is sufficient to cause scrapie in recipient sheep. Cell-sorted CD45R+ (predominantly B lymphocytes), CD4+/CD8+ (T lymphocytes), and CD14+ (monocytes/macrophages) blood cell subpopulations all were shown to contain prion infectivity by bioassays in ovine PrP transgenic mice. However, while the intravenous administration of 106 CD45+ or CD4+/8+ living cells was able to transmit the disease, similar numbers of CD14+ cells failed to infect the recipients. These data support the contention that mononucleated blood cell populations display different abilities to transmit TSE by the transfusion route. They also represent an important input for the risk assessment of blood-borne prion disease transmission and for refining the target performance of leukoreduction processes that currently are applied to mitigate the transmission risk in transfusion medicine. IMPORTANCE Interindividual variant Creutzfeldt-Jakob disease (vCJD) transmission through blood and blood-derived products is considered a major public health issue in transfusion medicine. Over the last decade, TSE in sheep has emerged as a

  19. Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years

    PubMed Central

    Jaunmuktane, Zane; Adlard, Peter; Bjurstrom, Nina; Caine, Diana; Lowe, Jessica; Norsworthy, Penny; Hummerich, Holger; Druyeh, Ron; Wadsworth, Jonathan D. F.; Brandner, Sebastian; Hyare, Harpreet; Mead, Simon; Collinge, John

    2015-01-01

    Patients with iatrogenic Creutzfeldt-Jakob disease due to administration of cadaver-sourced growth hormone during childhood are still being seen in the UK 30 years after cessation of this treatment. Of the 77 patients who have developed iatrogenic Creutzfeldt-Jakob disease, 56 have been genotyped. There has been a marked change in genotype profile at polymorphic codon 129 of the prion protein gene (PRNP) from predominantly valine homozygous to a mixed picture of methionine homozygous and methionine-valine heterozygous over time. The incubation period of iatrogenic Creutzfeldt-Jakob disease is significantly different between all three genotypes. This experience is a striking contrast with that in France and the USA, which may relate to contamination of different growth hormone batches with different strains of human prions. We describe the clinical, imaging, molecular and autopsy features in 22 of 24 patients who have developed iatrogenic Creutzfeldt-Jakob disease in the UK since 2003. Mean age at onset of symptoms was 42.7 years. Gait ataxia and lower limb dysaesthesiae were the most frequent presenting symptoms. All had cerebellar signs, and the majority had myoclonus and lower limb pyramidal signs, with relatively preserved cognitive function, when first seen. There was a progressive decline in neurological and cognitive function leading to death after 5–32 (mean 14) months. Despite incubation periods approaching 40 years, the clinical duration in methionine homozygote patients appeared to be shorter than that seen in heterozygote patients. MRI showed restricted diffusion in the basal ganglia, thalamus, hippocampus, frontal and the paracentral motor cortex and cerebellar vermis. The electroencephalogram was abnormal in 15 patients and cerebrospinal fluid 14-3-3 protein was positive in half the patients. Neuropathological examination was conducted in nine patients. All but one showed synaptic prion deposition with numerous kuru type plaques in the basal ganglia

  20. Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years.

    PubMed

    Rudge, Peter; Jaunmuktane, Zane; Adlard, Peter; Bjurstrom, Nina; Caine, Diana; Lowe, Jessica; Norsworthy, Penny; Hummerich, Holger; Druyeh, Ron; Wadsworth, Jonathan D F; Brandner, Sebastian; Hyare, Harpreet; Mead, Simon; Collinge, John

    2015-11-01

    Patients with iatrogenic Creutzfeldt-Jakob disease due to administration of cadaver-sourced growth hormone during childhood are still being seen in the UK 30 years after cessation of this treatment. Of the 77 patients who have developed iatrogenic Creutzfeldt-Jakob disease, 56 have been genotyped. There has been a marked change in genotype profile at polymorphic codon 129 of the prion protein gene (PRNP) from predominantly valine homozygous to a mixed picture of methionine homozygous and methionine-valine heterozygous over time. The incubation period of iatrogenic Creutzfeldt-Jakob disease is significantly different between all three genotypes. This experience is a striking contrast with that in France and the USA, which may relate to contamination of different growth hormone batches with different strains of human prions. We describe the clinical, imaging, molecular and autopsy features in 22 of 24 patients who have developed iatrogenic Creutzfeldt-Jakob disease in the UK since 2003. Mean age at onset of symptoms was 42.7 years. Gait ataxia and lower limb dysaesthesiae were the most frequent presenting symptoms. All had cerebellar signs, and the majority had myoclonus and lower limb pyramidal signs, with relatively preserved cognitive function, when first seen. There was a progressive decline in neurological and cognitive function leading to death after 5-32 (mean 14) months. Despite incubation periods approaching 40 years, the clinical duration in methionine homozygote patients appeared to be shorter than that seen in heterozygote patients. MRI showed restricted diffusion in the basal ganglia, thalamus, hippocampus, frontal and the paracentral motor cortex and cerebellar vermis. The electroencephalogram was abnormal in 15 patients and cerebrospinal fluid 14-3-3 protein was positive in half the patients. Neuropathological examination was conducted in nine patients. All but one showed synaptic prion deposition with numerous kuru type plaques in the basal ganglia

  1. Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases.

    PubMed

    Kabir, M Enamul; Safar, Jiri G

    2014-01-01

    There is a growing body of evidence indicating that number of human neurodegenerative diseases, including Alzheimer disease, Parkinson disease, fronto-temporal dementias, and amyotrophic lateral sclerosis, propagate in the brain via prion-like intercellular induction of protein misfolding. Prions cause lethal neurodegenerative diseases in humans, the most prevalent being sporadic Creutzfeldt-Jakob disease (sCJD); they self-replicate and spread by converting the cellular form of prion protein (PrP(C)) to a misfolded pathogenic conformer (PrP(Sc)). The extensive phenotypic heterogeneity of human prion diseases is determined by polymorphisms in the prion protein gene, and by prion strain-specific conformation of PrP(Sc). Remarkably, even though informative nucleic acid is absent, prions may undergo rapid adaptation and evolution in cloned cells and upon crossing the species barrier. In the course of our investigation of this process, we isolated distinct populations of PrP(Sc) particles that frequently co-exist in sCJD. The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability. Exposed to mutant substrate, the winning PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability. Thus, the evolution and adaptation of human prions is enabled by a dynamic collection of distinct populations of particles, whose evolution is governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. This fundamental biological mechanism may explain the drug resistance that some prions gained after exposure to compounds targeting PrP(Sc). Whether the phenotypic heterogeneity of other neurodegenerative diseases caused by protein misfolding is determined by the spectrum of misfolded conformers (strains) remains to be established. However, the prospect that these conformers may evolve and

  2. Outcome measures in inflammatory rheumatic diseases

    PubMed Central

    2009-01-01

    Inflammatory rheumatic diseases are generally multifaceted disorders and, therefore, measurement of multiple outcomes is relevant to most of these diseases. Developments in outcome measures in the rheumatic diseases are promoted by the development of successful treatments. Outcome measurement will increasingly deal with measurement of low levels of disease activity and avoidance of disease consequences. It is an advantage for patient management and knowledge transfer if the same outcomes are used in practice and in trials. Continuous measures of change are generally the most powerful and, therefore, are preferred as primary outcomes in trials. For daily clinical practice, outcome measures should reflect the patients' state and have to be easily derivable. The objective of this review is to describe recent developments in outcome measures for inflammatory rheumatic diseases for trials and clinical practice, with an emphasis on rheumatoid arthritis. PMID:19849821

  3. Cows for fear: is BSE a threat to human health? Bovine spongiform encephalopathy.

    PubMed Central

    Josephson, J

    1998-01-01

    In 1996, a new variant of Creutzfeldt-Jakob disease (vCJD)-a disease that causes lack of coordination, muscle twitching or jerking, dementia, and, eventually, death-suddenly appeared in Great Britain. It is believed that the victims contracted the disease from eating the beef of cattle stricken with bovine spongiform encephalopathy (BSE), or mad cow disease. As of December 1997, at least 25 people in the United Kingdom and France have contracted vCJD. PMID:9485478

  4. [Investigation of the clinical course and treatment of prion disease patients in the akinetic mutism state in Japan].

    PubMed

    Iwasaki, Yasushi; Mori, Keiko; Ito, Masumi

    2012-01-01

    Twelve cases (one Gerstmann-Sträussler-Scheinker syndrome (P102L; definite), one genetic Creutzfeldt-Jakob disease (CJD) (V180I; definite) and ten sporadic CJD (7 MM1-type definite, 3 probable)), who reached the akinetic mutism state, were investigated with regard to their clinical course and treatment. They were hospitalized for a total of 3,968 days in the akinetic mutism state. In the nine definite cases, the median period from the akinetic mutism state to death was 22 months (average: 27.0 ± 23.3 months, range: 3-80 months) and median total disease duration was 27 months (average: 34.2 ± 30.1 months, range: 5-102 months). In the seven definite sporadic CJD cases, the median period from akinetic mutism to death was 21 months (average: 17.0 ± 9.6 months, range 3-28 months), and median total disease duration was 24 months (average: 20.6 ± 10.0 months, range: 5-31 months). Nasal-tube feeding was performed in all cases. Symptomatic treatments such as parenteral nutrition and antibiotic drugs were administered for complications such as respitory and urinary tract infections and digestive symptoms. Patients received rehabilitation and hot spring therapy regularly until death. Gastrostomy and/or tracheotomy was not performed in any case, the patients were not intubated nor was mechanical ventilation (including non-invasive positive pressure ventilation) applied. Vasoactive drugs were not administered. Clonazepam was administered for myoclonus in four patients but not in another three when myoclonus appeared. It is unclear whether the treatment influenced the duration of myoclonus. Our observations indicate that the extended survival period among Japanese prion disease patients is likely due to the management procedures implemented for prion disease in Japan, which are usually continued after the patients reach the akinetic mutism state. We speculate that nasal-tube feeding is the crucial factor that results in the prolonged disease duration of prion disease

  5. Cortical sensory loss in a patient with posterior cortical atrophy: a case report.

    PubMed

    Hsu, Jung-Lung; Chen, Wei-Hung; Chiu, Hou-Chang

    2004-02-01

    Patients with posterior cortical atrophy (PCA) who present with initial symptoms of higher visual function deficits eventually develop alexia, aphasia, and components of Balint's syndrome or Gerstmann's syndrome. Recently, pathological findings were reported for these patients that are generally suggestive of Alzheimer's disease even though Creutzfeldt-Jakob disease (CJD) was presumed as an alternative cause of some autopsy-diagnosed PCA cases. Here, we report a case with a four-year progression of cognitive and higher visual function deterioration, and with features not described in previously reported PCA cases (i.e., a distinct sensory complaint and early frontal lobe involvement). To summarize, this case belongs to perceptual-motor syndrome of asymmetric cortical degeneration and the underlying neuropathology is more suggestive of Alzheimer's disease than of Creutzfeldt-Jakob disease.

  6. Diagnosis and Evaluation of a Patient with Rapidly Progressive Dementia

    PubMed Central

    Bucelli, Robert C.; Ances, Beau M.

    2014-01-01

    While the most common dementia is Alzheimer’s disease (AD), a detailed history is needed to rule out rapidly progressive dementias (RPDs). RPDs are less than two years in duration and have a rate of progression faster typical neurodegenerative diseases. Identification of RPDs is important as some are treatable. This review focuses on the spectrum of RPDs, with special emphasis on paraneoplastic disorders and Creutzfeldt-Jakob disease (CJD). PMID:24279195

  7. Transplantation of Cadaver Tissues and Organs. Part 15. Chapter 338

    DTIC Science & Technology

    1984-01-09

    AG, Streeten B, Cowen D: Possible "p~rson-to-person transmission of Creutzfeldt - Jakob disease . N Engl J Med 290:692-693, 1974. 5. Friediaender GE... Jakob disease following corneal transplantation (4,7), as well as the virus of hepatitis transmitted through allogeneic bone (15). Aseptic procurement...iwperatives: to care for the patient whose brain is devastated by trauma or disease ; and when efforts at reversing the In- exorable course of cerebral

  8. Prion Transport to Secondary Lymphoreticular System Tissues

    DTIC Science & Technology

    2007-06-01

    Desbruslais, M., Luthert, P.J., & Collinge, J. (2001). Tissue Distribution of protease resistant prion protein in variant Creutzfeldt - Jakob disease ...examine the disease development of a prion strain (DY TME) that does not replicate in the spleen of hamsters. This system will provide details into the...gender specific responses to intraperitoneal DY TME inoculation. 15. SUBJECT TERMS Prion diseases , macrophage, complement 16. SECURITY

  9. Computer measurement of arterial disease

    NASA Technical Reports Server (NTRS)

    Armstrong, J.; Selzer, R. H.; Barndt, R.; Blankenhorn, D. H.; Brooks, S.

    1980-01-01

    Image processing technique quantifies human atherosclerosis by computer analysis of arterial angiograms. X-ray film images are scanned and digitized, arterial shadow is tracked, and several quantitative measures of lumen irregularity are computed. In other tests, excellent agreement was found between computer evaluation of femoral angiograms on living subjects and evaluation by teams of trained angiographers.

  10. Discovering protein similarity using natural language processing.

    PubMed Central

    Sarkar, Indra N.; Rindflesch, Thomas C.

    2002-01-01

    Extracting protein interaction relationships from textual repositories, such as MEDLINE, may prove useful in generating novel biological hypotheses. Using abstracts relevant to two known functionally related proteins, we modified an existing natural language processing tool to extract protein interaction terms. We were able to obtain functional information about two proteins, Amyloid Precursor Protein and Prion Protein, that have been implicated in the etiology of Alzheimer's Disease and Creutzfeldt-Jakob Disease, respectively. PMID:12463910

  11. Uptake and Degradation of Protease-Sensitive and -Resistant Forms of Abnormal Human Prion Protein Aggregates by Human Astrocytes

    PubMed Central

    Choi, Young Pyo; Head, Mark W.; Ironside, James W.; Priola, Suzette A.

    2015-01-01

    Sporadic Creutzfeldt-Jakob disease is the most common of the human prion diseases, a group of rare, transmissible, and fatal neurologic diseases associated with the accumulation of an abnormal form (PrPSc) of the host prion protein. In sporadic Creutzfeldt-Jakob disease, disease-associated PrPSc is present not only as an aggregated, protease-resistant form but also as an aggregated protease-sensitive form (sPrPSc). Although evidence suggests that sPrPSc may play a role in prion pathogenesis, little is known about how it interacts with cells during prion infection. Here, we show that protease-sensitive abnormal PrP aggregates derived from patients with sporadic Creutzfeldt-Jakob disease are taken up and degraded by immortalized human astrocytes similarly to abnormal PrP aggregates that are resistant to proteases. Our data suggest that relative proteinase K resistance does not significantly influence the astrocyte's ability to degrade PrPSc. Furthermore, the cell does not appear to distinguish between sPrPSc and protease-resistant PrPSc, suggesting that sPrPSc could contribute to prion infection. PMID:25280631

  12. Use of containment pans and lids for autoclaving caustic solutions.

    PubMed

    Brown, Stanley A; Merritt, Katharine

    2003-06-01

    As a means of decontaminating instruments possibly exposed to Creutzfeldt-Jakob disease, the World Health Organization has recommended immersion and autoclaving in sodium hydroxide. However, this recommendation has raised concerns of possible damage to autoclaves, and hazards to operators as a result of the caustic vapors. A series of experiments has been conducted that demonstrate that there are containment pan-and-lid combinations in which instruments can be autoclaved in sodium hydroxide without risk to the autoclave or the operator.

  13. Effects of Hydrazines upon Cyclic Nucleotide Regulated Neuronal Processes

    DTIC Science & Technology

    1987-07-30

    of adenylate cyclase, however, Creutzfeldt-Jakob disease (CJD) is a slow, infec- in neuronal membranes this enzyme can be tious, progressive...61102F 2312 UPONI CYFCLIC NECLEOTIDE REGULATED NEURONAL RESP+SES 12. PORSONAIL AUTMORIS) Mark MI. Rasenick, Ph.D. 934L TYPE OF REPORT 131m. Time...CT TERMI AS Icon hN.. on powe"~ 4f mete~up *ad Idendfy by. Week mum Imr) "peLo GROUP sun. owr Neuronal Signal, Transduction, Cytoskeleton

  14. Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients.

    PubMed

    Mills, James L; Schonberger, Lawrence B; Wysowski, Diane K; Brown, Paul; Durako, Stephen J; Cox, Christopher; Kong, Fanhui; Fradkin, Judith E

    2004-04-01

    Patients who received pituitary-derived growth hormone (GH) are at excess risk of mortality from Creutzfeldt-Jakob disease. We investigated whether they were at increased risk of death from other conditions, particularly preventable conditions. A cohort (N=6107) from known US pituitary-derived GH recipients (treated 1963-1985) was studied. Deaths were identified by reports from physicians and parents and the National Death Index. Rates were compared with the expected rates for the US population standardized for race, age, and sex. There were 433 deaths versus 114 expected (relative risk [RR], 3.8; 95% confidence interval [CI], 3.4-4.2; P<.0001) from 1963 through 1996. Risk was increased in subjects with GH deficiency caused by any tumor (RR, 10.4; 95% CI, 9.1-12.0; P<.0001). Surprisingly, subjects with hypoglycemia treated within the first 6 months of life were at extremely high risk (RR, 18.3; 95% CI, 9.2-32.8; P<.0001), as were all subjects with adrenal insufficiency (RR, 7.1; 95% CI, 6.2-8.2; P<.0001). A quarter of all deaths were sudden and unexpected. Of the 26 cases of Creutzfeldt-Jakob disease, four cases have died since 2000. The death rate in pituitary-derived GH recipients was almost four times the expected rate. Replacing pituitary-derived GH with recombinant GH has eliminated only the risk of Creutzfeldt-Jakob disease. Hypoglycemia and adrenal insufficiency accounted for far more mortality than Creutzfeldt-Jakob disease. The large number of potentially preventable deaths in patients with adrenal insufficiency and hypoglycemia underscores the importance of early intervention when infection occurs in patients with adrenal insufficiency, and aggressive treatment of panhypopituitarism.

  15. Nosocomial viral infections: III. Guidelines for prevention and control of exanthematous viruses, gastroenteritis viruses, picornaviruses, and uncommonly seen viruses.

    PubMed

    Valenti, W M; Hruska, J F; Menegus, M A; Freeburn, M J

    1981-01-01

    This communication is the third in a four-part series on nosocomial viral infections from the Strong Memorial Hospital. This third article discusses guidelines for prevention and control of exanthematous viruses, gastroenteritis, viruses, adenoviruses and the picornaviruses other than rhinoviruses. Several uncommonly seen viruses, such as the virus of Creutzfeldt-Jakob disease and Marburg, Ebola, and Lassa fever viruses, also are reviewed briefly.

  16. Diagnosis of Human Prion Disease Using Real-Time Quaking-Induced Conversion Testing of Olfactory Mucosa and Cerebrospinal Fluid Samples.

    PubMed

    Bongianni, Matilde; Orrù, Christina; Groveman, Bradley R; Sacchetto, Luca; Fiorini, Michele; Tonoli, Giovanni; Triva, Giorgio; Capaldi, Stefano; Testi, Silvia; Ferrari, Sergio; Cagnin, Annachiara; Ladogana, Anna; Poleggi, Anna; Colaizzo, Elisa; Tiple, Dorina; Vaianella, Luana; Castriciano, Santina; Marchioni, Daniele; Hughson, Andrew G; Imperiale, Daniele; Cattaruzza, Tatiana; Fabrizi, Gian Maria; Pocchiari, Maurizio; Monaco, Salvatore; Caughey, Byron; Zanusso, Gianluigi

    2017-02-01

    Early and accurate in vivo diagnosis of Creutzfeldt-Jakob disease (CJD) is necessary for quickly distinguishing treatable from untreatable rapidly progressive dementias and for future therapeutic trials. This early diagnosis is becoming possible using the real-time quaking-induced conversion (RT-QuIC) seeding assay, which detects minute amounts of the disease-specific pathologic prion protein in cerebrospinal fluid (CSF) or olfactory mucosa (OM) samples. To develop an algorithm for accurate and early diagnosis of CJD by using the RT-QuIC assay on CSF samples, OM samples, or both. In this case-control study, samples of CSF and OM were collected from 86 patients with a clinical diagnosis of probable (n = 51), possible (n = 24), or suspected (n = 11) CJD and 104 negative control samples (54 CSF and 50 OM). The CSF and OM samples were analyzed using conventional RT-QuIC. The CSF samples underwent further testing using improved RT-QuIC conditions. In addition, the diagnostic performance of a novel, easy-to-use, gentle flocked swab for sampling of OM was evaluated. Data were collected from January 1 to June 30, 2015. Correlations between RT-QuIC results and the final diagnosis of recruited patients. Among the 86 patients (37 men [43%] and 49 women [57%]; mean [SD] age, 65.7 [11.5] years) included for analysis, all 61 patients with sporadic CJD had positive RT-QuIC findings using OM or CSF samples or both for an overall RT-QuIC diagnostic sensitivity of 100% (95% CI, 93%-100%). All patients with a final diagnosis of non-prion disease (71 CSF and 67 OM samples) had negative RT-QuIC findings for 100% specificity (95% CI, 94%-100%). Of 8 symptomatic patients with various mutations causing CJD or Gerstmann-Sträussler-Scheinker syndrome, 6 had positive and 2 had negative RT-QuIC findings for a sensitivity of 75% (95% CI, 36%-96%). A proposed diagnostic algorithm for sporadic CJD combines CSF and OM RT-QuIC testing to provide virtually 100% diagnostic sensitivity

  17. Preventive health measures in inflammatory bowel disease

    PubMed Central

    Abegunde, Ayokunle T; Muhammad, Bashir H; Ali, Tauseef

    2016-01-01

    We aim to review the literature and provide guidance on preventive health measures in inflammatory bowel disease (IBD). Structured searches were performed in PubMed, MEDLINE, EMBASE, Web of Science and Cochrane Library from January 1976 to June 2016 using the following keywords: (inflammatory bowel disease OR Crohn’s disease OR ulcerative colitis) AND (health maintenance OR preventive health OR health promotion). Abstracts of the articles selected from each of these multiple searches were reviewed, and those meeting the inclusion criteria (that is, providing data regarding preventive health or health maintenance in IBD patients) were recorded. Reference lists from the selected articles were manually reviewed to identify further relevant studies. Patients with IBD are at increased risk of developing adverse events related to the disease course, therapeutic interventions, or non-adherence to medication. Recent studies have suggested that IBD patients do not receive preventive services with the same thoroughness as patients with other chronic diseases. Preventive health measures can avert morbidity and improve the quality of life of patients with IBD. Gastroenterologists and primary care physicians (PCPs) should have an up to date working knowledge of preventive health measures for IBD patients. A holistic approach and better communication between gastroenterologists and PCPs with explicit clarification of roles will prevent duplication of services and streamline care. PMID:27678347

  18. Preventive health measures in inflammatory bowel disease.

    PubMed

    Abegunde, Ayokunle T; Muhammad, Bashir H; Ali, Tauseef

    2016-09-14

    We aim to review the literature and provide guidance on preventive health measures in inflammatory bowel disease (IBD). Structured searches were performed in PubMed, MEDLINE, EMBASE, Web of Science and Cochrane Library from January 1976 to June 2016 using the following keywords: (inflammatory bowel disease OR Crohn's disease OR ulcerative colitis) AND (health maintenance OR preventive health OR health promotion). Abstracts of the articles selected from each of these multiple searches were reviewed, and those meeting the inclusion criteria (that is, providing data regarding preventive health or health maintenance in IBD patients) were recorded. Reference lists from the selected articles were manually reviewed to identify further relevant studies. Patients with IBD are at increased risk of developing adverse events related to the disease course, therapeutic interventions, or non-adherence to medication. Recent studies have suggested that IBD patients do not receive preventive services with the same thoroughness as patients with other chronic diseases. Preventive health measures can avert morbidity and improve the quality of life of patients with IBD. Gastroenterologists and primary care physicians (PCPs) should have an up to date working knowledge of preventive health measures for IBD patients. A holistic approach and better communication between gastroenterologists and PCPs with explicit clarification of roles will prevent duplication of services and streamline care.

  19. Optimising mobility outcome measures in Huntington's disease.

    PubMed

    Busse, Monica; Quinn, Lori; Khalil, Hanan; McEwan, Kirsten

    2014-01-01

    Many of the performance-based mobility measures that are currently used in Huntington's disease (HD) were developed for assessment in other neurological conditions such as stroke. We aimed to assess the individual item-response of commonly used performance-based mobility measures, with a view to optimizing the scales for specific application in Huntington's Disease (HD). Data from a larger multicentre, observational study were used. Seventy-five people with HD (11 pre-manifest & 64 manifest) were assessed on the Six-Minute Walk Test, 10-Meter Walk Test, Timed "Up & Go" Test (TUG), Berg Balance Scale (BBS), Physical Performance Test (PPT), Four Square Step Test, and Tinetti Mobility Test (TMT). The Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, Functional Assessment Scale and Total Functional Capacity scores were recorded, alongside cognitive measures. Standard regression analysis was used to assess predictive validity. Individual item responses were investigated using a sequence of approaches to allow for gradual removal of items and the subsequent creation of shortened versions. Psychometric properties (reliability and discriminant ability) of the shortened scales were assessed. TUG (β 0.46, CI 0.20-3.47), BBS (β -0.35, CI -2.10-0.14), and TMT (β -0.45, CI -3.14-0.64) were good disease-specific mobility measures. PPT was the best measure of functional performance (β 0.42, CI 0.00-0.43 for TFC & β 0.57 CI 0.15-0.81 for FAS). Shortened versions of BBS and TMT were developed based on item analysis. The resultant BBS and TMT shortened scales were reliable for use in manifest HD. ROC analysis showed that shortened scales were able to discriminate between manifest and pre-manifest disease states. Our data suggests that the PPT is appropriate as a general measure of function in individuals with HD, and we have identified shortened versions of the BBS and TMT that measure the unique gait and balance impairments in HD. These scales, alongside the

  20. Measuring Spatial Dependence for Infectious Disease Epidemiology.

    PubMed

    Lessler, Justin; Salje, Henrik; Grabowski, M Kate; Cummings, Derek A T

    2016-01-01

    Global spatial clustering is the tendency of points, here cases of infectious disease, to occur closer together than expected by chance. The extent of global clustering can provide a window into the spatial scale of disease transmission, thereby providing insights into the mechanism of spread, and informing optimal surveillance and control. Here the authors present an interpretable measure of spatial clustering, τ, which can be understood as a measure of relative risk. When biological or temporal information can be used to identify sets of potentially linked and likely unlinked cases, this measure can be estimated without knowledge of the underlying population distribution. The greater our ability to distinguish closely related (i.e., separated by few generations of transmission) from more distantly related cases, the more closely τ will track the true scale of transmission. The authors illustrate this approach using examples from the analyses of HIV, dengue and measles, and provide an R package implementing the methods described. The statistic presented, and measures of global clustering in general, can be powerful tools for analysis of spatially resolved data on infectious diseases.

  1. [Variability of efficacy measures in Alzheimer's disease].

    PubMed

    Musicco, Massimo; Pettenati, Carla; Caltagirone, Carlo

    2005-01-01

    The efficacy of medical interventions is their capacity of inducing positive modifications of the natural history of diseases. The natural history of dementia is marked by specific events related to the cognitive and functional decline, but their occurrence is poorly predictable in individual patients being highly variable from patient to patient. For this reason it is difficult that the modest efficacy of available interventions for dementia, or their entity measured by clinical scales, may be perceived in clinical practice or in observational studies. Moreover in randomized clinical studies, the effect of this variability, in analogy to misclassification of exposition and/or disease in case control or cohort epidemiological studies, is that of an underestimation of the true efficacy of interventions.

  2. Parkinson's disease detection based on dysphonia measurements

    NASA Astrophysics Data System (ADS)

    Lahmiri, Salim

    2017-04-01

    Assessing dysphonic symptoms is a noninvasive and effective approach to detect Parkinson's disease (PD) in patients. The main purpose of this study is to investigate the effect of different dysphonia measurements on PD detection by support vector machine (SVM). Seven categories of dysphonia measurements are considered. Experimental results from ten-fold cross-validation technique demonstrate that vocal fundamental frequency statistics yield the highest accuracy of 88 % ± 0.04. When all dysphonia measurements are employed, the SVM classifier achieves 94 % ± 0.03 accuracy. A refinement of the original patterns space by removing dysphonia measurements with similar variation across healthy and PD subjects allows achieving 97.03 % ± 0.03 accuracy. The latter performance is larger than what is reported in the literature on the same dataset with ten-fold cross-validation technique. Finally, it was found that measures of ratio of noise to tonal components in the voice are the most suitable dysphonic symptoms to detect PD subjects as they achieve 99.64 % ± 0.01 specificity. This finding is highly promising for understanding PD symptoms.

  3. Bovine spongiform encephalopathy: a tipping point in One Health and Food Safety.

    PubMed

    Hope, James

    2013-01-01

    Bovine spongiform encephalopathy (BSE) is a protein misfolding disease of cattle which belongs to the group of transmissible spongiform encephalopathies (TSEs) or prion diseases. This group also includes scrapie in sheep and goats, chronic wasting disease (CWD) of cervids and Creutzfeldt-Jakob disease (CJD) humans. The first case of BSE was recognised in England in 1986 as a progressive, neurological condition where affected animals behaved abnormally, exhibited anxiety, ataxia, hypersensitivity to touch and noise and poor body condition. Spongiform change was observed in the brain stem of cattle at post-mortem and its similarity to scrapie in sheep stimulated biochemical investigation and transmission studies which confirmed it as a novel prion disease of cattle. Epidemiological analysis of the initial cases of disease implicated a common extended source of infection, likely to be related to feed, and stimulated a series of control measures designed to restrict feeding of mammalian-derived protein to ruminants in various parts of the United Kingdom and to prevent the use of various bovine offals in feed or food production. This article outlines the rise and fall of the incidence of BSE in the UK and Europe, its classification as a zoonotic disease with the emergence of variant CJD, the implications of it as a prion disease and challenge its diagnosis and control continues to represent worldwide.

  4. The role of the NADPH oxidase NOX2 in prion pathogenesis.

    PubMed

    Sorce, Silvia; Nuvolone, Mario; Keller, Annika; Falsig, Jeppe; Varol, Ahmet; Schwarz, Petra; Bieri, Monika; Budka, Herbert; Aguzzi, Adriano

    2014-12-01

    Prion infections cause neurodegeneration, which often goes along with oxidative stress. However, the cellular source of reactive oxygen species (ROS) and their pathogenetic significance are unclear. Here we analyzed the contribution of NOX2, a prominent NADPH oxidase, to prion diseases. We found that NOX2 is markedly upregulated in microglia within affected brain regions of patients with Creutzfeldt-Jakob disease (CJD). Similarly, NOX2 expression was upregulated in prion-inoculated mouse brains and in murine cerebellar organotypic cultured slices (COCS). We then removed microglia from COCS using a ganciclovir-dependent lineage ablation strategy. NOX2 became undetectable in ganciclovir-treated COCS, confirming its microglial origin. Upon challenge with prions, NOX2-deficient mice showed delayed onset of motor deficits and a modest, but significant prolongation of survival. Dihydroethidium assays demonstrated a conspicuous ROS burst at the terminal stage of disease in wild-type mice, but not in NOX2-ablated mice. Interestingly, the improved motor performance in NOX2 deficient mice was already measurable at earlier stages of the disease, between 13 and 16 weeks post-inoculation. We conclude that NOX2 is a major source of ROS in prion diseases and can affect prion pathogenesis.

  5. The Role of the NADPH Oxidase NOX2 in Prion Pathogenesis

    PubMed Central

    Sorce, Silvia; Nuvolone, Mario; Keller, Annika; Falsig, Jeppe; Varol, Ahmet; Schwarz, Petra; Bieri, Monika; Budka, Herbert; Aguzzi, Adriano

    2014-01-01

    Prion infections cause neurodegeneration, which often goes along with oxidative stress. However, the cellular source of reactive oxygen species (ROS) and their pathogenetic significance are unclear. Here we analyzed the contribution of NOX2, a prominent NADPH oxidase, to prion diseases. We found that NOX2 is markedly upregulated in microglia within affected brain regions of patients with Creutzfeldt-Jakob disease (CJD). Similarly, NOX2 expression was upregulated in prion-inoculated mouse brains and in murine cerebellar organotypic cultured slices (COCS). We then removed microglia from COCS using a ganciclovir-dependent lineage ablation strategy. NOX2 became undetectable in ganciclovir-treated COCS, confirming its microglial origin. Upon challenge with prions, NOX2-deficient mice showed delayed onset of motor deficits and a modest, but significant prolongation of survival. Dihydroethidium assays demonstrated a conspicuous ROS burst at the terminal stage of disease in wild-type mice, but not in NOX2-ablated mice. Interestingly, the improved motor performance in NOX2 deficient mice was already measurable at earlier stages of the disease, between 13 and 16 weeks post-inoculation. We conclude that NOX2 is a major source of ROS in prion diseases and can affect prion pathogenesis. PMID:25502554

  6. Mononucleated Blood Cell Populations Display Different Abilities To Transmit Prion Disease by the Transfusion Route.

    PubMed

    Douet, Jean-Yves; Lacroux, Caroline; Litaise, Claire; Lugan, Séverine; Corbière, Fabien; Arnold, Mark; Simmons, Hugh; Aron, Naima; Costes, Pierrette; Tillier, Cécile; Cassard, Hervé; Andréoletti, Olivier

    2016-01-13

    Previous experiments carried out in a sheep scrapie model demonstrated that the transfusion of 200 μl of prion-infected whole blood has an apparent 100% efficacy for disease transmission. These experiments also indicated that, despite the apparent low infectious titer, the intravenous administration of white blood cells (WBC) resulted in efficient disease transmission. In the study presented here, using the same transmissible spongiform encephalopathy (TSE) animal model, our aim was to determine the minimal number of white blood cells and the specific abilities of mononucleated cell populations to transmit scrapie by the transfusion route. Our results confirmed that the transfusion of 100 μl, but not 10 μl, of fresh whole blood collected in asymptomatic scrapie-infected donor sheep can transmit the disease. The data also show that the intravenous administration of 10(5) WBCs is sufficient to cause scrapie in recipient sheep. Cell-sorted CD45R(+) (predominantly B lymphocytes), CD4(+)/CD8(+) (T lymphocytes), and CD14(+) (monocytes/macrophages) blood cell subpopulations all were shown to contain prion infectivity by bioassays in ovine PrP transgenic mice. However, while the intravenous administration of 10(6) CD45(+) or CD4(+)/8(+) living cells was able to transmit the disease, similar numbers of CD14(+) cells failed to infect the recipients. These data support the contention that mononucleated blood cell populations display different abilities to transmit TSE by the transfusion route. They also represent an important input for the risk assessment of blood-borne prion disease transmission and for refining the target performance of leukoreduction processes that currently are applied to mitigate the transmission risk in transfusion medicine. Interindividual variant Creutzfeldt-Jakob disease (vCJD) transmission through blood and blood-derived products is considered a major public health issue in transfusion medicine. Over the last decade, TSE in sheep has emerged as a

  7. Amyloid Structure and Assembly: Insights from Scanning Transmission Electron Microscopy

    SciTech Connect

    Goldsbury, C.; Wall, J.; Baxa, U.; Simon, M. N.; Steven, A. C.; Engel, A.; Aebi, U.; Muller, S. A.

    2011-01-01

    Amyloid fibrils are filamentous protein aggregates implicated in several common diseases such as Alzheimer's disease and type II diabetes. Similar structures are also the molecular principle of the infectious spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, scrapie in sheep, and of the so-called yeast prions, inherited non-chromosomal elements found in yeast and fungi. Scanning transmission electron microscopy (STEM) is often used to delineate the assembly mechanism and structural properties of amyloid aggregates. In this review we consider specifically contributions and limitations of STEM for the investigation of amyloid assembly pathways, fibril polymorphisms and structural models of amyloid fibrils. This type of microscopy provides the only method to directly measure the mass-per-length (MPL) of individual filaments. Made on both in vitro assembled and ex vivo samples, STEM mass measurements have illuminated the hierarchical relationships between amyloid fibrils and revealed that polymorphic fibrils and various globular oligomers can assemble simultaneously from a single polypeptide. The MPLs also impose strong constraints on possible packing schemes, assisting in molecular model building when combined with high-resolution methods like solid-state nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR).

  8. Amyloid Structure and Assembly: Insights from Scanning Transmission Electron Microscopy

    PubMed Central

    Goldsbury, Claire; Baxa, Ulrich; Simon, Martha N.; Steven, Alasdair C.; Engel, Andreas; Wall, Joseph S.; Aebi, Ueli; Müller, Shirley A.

    2010-01-01

    Amyloid fibrils are filamentous protein aggregates implicated in several common diseases like Alzheimer’s disease and type II diabetes. Similar structures are also the molecular principle of the infectious spongiform encephalopathies like Creutzfeldt-Jakob disease in humans, scrapie in sheep, and of the so-called yeast prions, inherited non-chromosomal elements found in yeast and fungi. Scanning transmission electron microscopy (STEM) is often used to delineate the assembly mechanism and structural properties of amyloid aggregates. In this review we consider specifically contributions and limitations of STEM for the investigation of amyloid assembly pathways, fibril polymorphisms and structural models of amyloid fibrils. This type of microscopy provides the only method to directly measure the mass-per-length (MPL) of individual filaments. Made on both in vitro assembled and ex vivo samples, STEM mass measurements have illuminated the hierarchical relationships between amyloid fibrils and revealed that polymorphic fibrils and various globular oligomers can assemble simultaneously from a single polypeptide. The MPLs also impose strong constraints on possible packing schemes, assisting in molecular model building when combined with high-resolution methods like solid-state nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR). PMID:20868754

  9. Amyloid structure and assembly: insights from scanning transmission electron microscopy.

    PubMed

    Goldsbury, Claire; Baxa, Ulrich; Simon, Martha N; Steven, Alasdair C; Engel, Andreas; Wall, Joseph S; Aebi, Ueli; Müller, Shirley A

    2011-01-01

    Amyloid fibrils are filamentous protein aggregates implicated in several common diseases such as Alzheimer's disease and type II diabetes. Similar structures are also the molecular principle of the infectious spongiform encephalopathies such as Creutzfeldt-Jakob disease in humans, scrapie in sheep, and of the so-called yeast prions, inherited non-chromosomal elements found in yeast and fungi. Scanning transmission electron microscopy (STEM) is often used to delineate the assembly mechanism and structural properties of amyloid aggregates. In this review we consider specifically contributions and limitations of STEM for the investigation of amyloid assembly pathways, fibril polymorphisms and structural models of amyloid fibrils. This type of microscopy provides the only method to directly measure the mass-per-length (MPL) of individual filaments. Made on both in vitro assembled and ex vivo samples, STEM mass measurements have illuminated the hierarchical relationships between amyloid fibrils and revealed that polymorphic fibrils and various globular oligomers can assemble simultaneously from a single polypeptide. The MPLs also impose strong constraints on possible packing schemes, assisting in molecular model building when combined with high-resolution methods like solid-state nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR). Copyright © 2010 Elsevier Inc. All rights reserved.

  10. The human transmissible spongiform encephalopathies (TSEs): implications for dental practitioners.

    PubMed

    Porter, S; Scully, C; Ridgway, G L; Bell, J

    2000-04-22

    Transmissible spongiform encephalopathies (TSEs) are rare, fatal degenerative brain diseases which affect humans and certain animals, and are caused by inheritance or acquisition of prions (PrPs). Inherited TSEs include Fatal Familial Insomnia (FFI), Gerstmann-Straussler-Scheinker syndrome (GSS) and other less well clinically characterised disorders, while the human infective TSEs include sporadic, iatrogenic and variant Creutzfeldt-Jakob disease (vCJD). The causative prions are found especially in neural tissues and spinal fluid, and in the case of vCJD, in lymphoreticular tissue. Available epidemiological evidence suggests that normal social or routine clinical contact with affected patients does not present a risk to health care workers, relatives or the community. Isolation of patients is not considered necessary. Nevertheless as the prions are resistant to conventional chemical, irradiation and heat sterilisation methods, highly specific cross-infection control measures are required for the dental management of patients with, or at notable risk, of TSE. The present article reviews current knowledge of the clinical consequences of prion disease and provides information regarding necessary changes to the cross-infection routine when managing patients infected, or at risk of, prion disease.

  11. Transmission of scrapie by steel-surface-bound prions.

    PubMed Central

    Flechsig, E.; Hegyi, I.; Enari, M.; Schwarz, P.; Collinge, J.; Weissmann, C.

    2001-01-01

    BACKGROUND: Prions are unusually resistant to conventional disinfection procedures. An electrode used intracerebrally on a Creutzfeldt-Jakob disease (CJD) patient transmitted the disease to two patients in succession and finally to a chimpanzee, despite attempted disinfection. Concerns that surgical instruments may transmit variant CJD have been raised by the finding of PrP(Sc), a surrogate marker for infectivity, in various tissues other than brain. MATERIALS AND METHODS: Stainless steel wire was exposed to scrapie-infected brain or brain homogenate, washed exhaustively and inserted into the brain of indicator mice to measure infectivity. RESULTS: A contact time of 5 min with scrapie-infected mouse brain suffices to render steel wire highly infectious and insertion of infectious wire into the brain of an indicator mouse for 30 min suffices to cause disease. Infectivity bound to wires persists far longer in the brain than when injected as homogenate, which can explain the extraordinary efficiency of wire-mediated infection. No detectable amounts of PrP could be eluted with NaOH, however the presence of PrP on infectious wires was demonstrated by chemiluminescence. Several recommended sterilisation procedures inactivated wire-bound mouse prions, but exposure to 10% formaldehyde was insufficient. CONCLUSIONS: Prions are readily and tightly bound to stainless steel surfaces and can transmit scrapie to recipient mice after short exposure times. This system mimics contaminated surgical instruments and will allow an assessment of sterilisation procedures. PMID:11713367

  12. Prion protein in patients with renal failure.

    PubMed

    Starke, R; Mackie, I; Drummond, O; MacGregor, I; Harrison, P; Machin, S

    2006-06-01

    We previously found elevated levels of prion protein (PrP(C)) in the blood plasma of 16 patients with renal failure. We studied a further 20 patients with renal failure, and all had a significantly higher PrP(C) concentration than healthy normal subjects (P < 0.0001). Renal dialysis did not remove plasma PrP(C) in these patients. Because dialysis patients receive heparin during dialysis, which could potentially bind to PrP(C), the concentration of PrP(C) was measured in patients receiving heparin for cardiopulmonary bypass and was found to be similar to normal controls. We also studied several other groups with chronic illnesses and found that patients with thrombotic thrombocytopenic purpura and sickle cell anaemia had normal plasma PrP(C) levels, but that those with beta-thalassaemia had slightly elevated levels of plasma PrP(C). This suggests that the observations in renal failure were not just part of a generalized response to chronic illness or acute phase reaction. The mechanism of elevated plasma PrP(C) levels in renal disease is unknown, but this shows that plasma PrP(C) is not a specific marker of neurological disease or Creutzfeldt-Jakob disease.

  13. The management of blood safety in the presence of uncertain risk: a United kingdom perspective.

    PubMed

    Watkins, Nicholas A; Dobra, Stephen; Bennett, Peter; Cairns, John; Turner, Marc L

    2012-07-01

    Millions of patients in the UK benefit from the use of both plasma derivatives and blood components that are seen as critical interventions in current medicine. Measures are in place to significantly reduce the risks associated with blood transfusion and plasma derivatives; however, these measures themselves are not risk free. Over the past 20 years, advances in technology and regulation have seen major reductions in the risks associated with transfusion. International blood services, industry, and regulators strive to maintain safety levels through constant monitoring, assessment, and response to changing risk factors. Regulation of screening tests together with the development and introduction of nucleic acid technique tests for hepatitis B virus, hepatitis C virus, and human immunodeficiency virus has improved blood safety. However, other risks, including the changing epidemiology of transfusion-transmitted infections, bacterial contamination of platelets, incorrect blood component transfusion, and variant Creutzfeldt-Jakob disease, require further attention. Risks such as these are often complex, and there is a difficult balance to be struck between donors/recipients' benefit and adequacy of blood supply. The introduction of any new safety measure therefore requires robust, evidence-based evaluation of associated benefit, both clinical and economical. This review presents a UK perspective on how the safety of the blood supply is maintained in the face of uncertain risks. Copyright © 2012. Published by Elsevier Inc.

  14. The molecular epidemiology of variant CJD

    PubMed Central

    Mackay, Graham A; Knight, Richard SG; Ironside, James W

    2011-01-01

    The emergence of the novel prion diseases bovine spongiform encephalopathy (BSE) and, subsequently, variant Creutzfeldt-Jakob disease (vCJD) in epidemic forms has attracted much scientific attention. The oral transmission of these disorders, the causative relationship of vCJD to BSE and the resistance of the transmissible agents in both disorders to conventional forms of decontamination has caused great public health concern. The size of the still emerging vCJD epidemic is thankfully much lower than some early published estimates. This paper reviews current knowledge of the factors that influence the development of vCJD: the properties of the infectious agent; the route of inoculation and individual susceptibility factors. The current epidemiological data are reviewed, along with relevant animal transmission studies. In terms of genetic susceptibility, the best characterised is the common single nucleotide polymorphism at codon 129 of prion protein gene. Current biomarkers and future areas of research will be discussed. These issues are important in informing precautionary measures and the ongoing monitoring of vCJD. PMID:21915360

  15. The price of the precautionary principle: cost-effectiveness of BSE intervention strategies in The Netherlands.

    PubMed

    Benedictus, A; Hogeveen, H; Berends, B R

    2009-06-01

    Since 1996, bovine spongiform encephalopathy (BSE) in cattle has been linked to a new variant of Creutzfeldt-Jakob disease (vCJD), a fatal brain disease in man. This paper assessed the cost-effectiveness of BSE control strategies instituted by the European Commission. In a Monte Carlo simulation model, a non-intervention baseline scenario was compared to three intervention strategies: removal of specified risk materials from slaughter animals, post-mortem testing for BSE and the culling of feed and age cohorts of BSE cases. The food risk in the baseline scenario ranged from 16.98 lost life years in 2002 to 2.69 lost life years in 2005. Removing specified risk materials removal practices, post-mortem testing and post-mortem testing plus cohort culling reduced this risk with 93%, 82.7% and 83.1%. The estimated cost-effectiveness of all BSE measures in The Netherlands ranged from 4.3 million euros per life year saved in 2002 to 17.7 million euros in 2005. It was discussed that the cost-effectiveness of BSE control strategies will further deviate from regular health economics thresholds as BSE prevalence and incidence declines.

  16. A prion primer

    PubMed Central

    Cashman, N R

    1997-01-01

    By biological and medical criteria, prions are infectious agents; however, many of their properties differ profoundly from those of conventional microbes. Prions are "encoded" by alterations in protein conformation rather than in nucleic acid or amino acid sequence. New epidemic prion diseases (bovine spongiform encephalopathy and new variant Creutzfeldt-Jakob disease) have recently emerged under the active surveillance of the modern world. The risk of contracting prion disease from blood products or other biologicals is now a focus of worldwide concern. Much has been discovered about prions and prion diseases, but much remains to be done. PMID:9371069

  17. Chronic disease management. Made to measure.

    PubMed

    Haggar, Tony

    2003-08-21

    Much of the emergency pressures faced by acute trusts result from patients with acute exacerbations of chronic illness. Progress can be made if greater emphasis is placed on managing the patient and their disease throughout the life-cycle. A new model of care was developed termed 'comprehensive care co-ordination'. The pilots suggest this model of care for the chronic illness could be rolled out quickly.

  18. How to measure the outcomes of chronic disease management.

    PubMed

    Lewis, Al

    2009-02-01

    The fastest-growing methodology for disease management outcomes measurement is valid, transparent, easy to apply, and freely available in the public domain and this article. It measures the actual goal of disease management, which is to reduce the rate of adverse events associated with the disease(s) being managed. Changes in this rate can be translated into a return on investment using some explicit assumptions about comorbidities and episode costs. Outcomes measured in this way show that in the health plan community as a whole, disease management in the broadest sense is working, as measured by the relative stability in the rate of adverse medical events closely associated with common chronic disease during this decade of increasing prevalence of most of the common chronic conditions.

  19. Health, well-being, and measuring the burden of disease

    PubMed Central

    2012-01-01

    This essay asks whether the global burden of diseases, injuries, and risk factors (GBD) should be measured in terms of their consequences for health, as maintained by most of those who are attempting to measure the GBD, or in terms of their consequences for well-being, as argued by John Broome. It answers that the burden of disease should be understood in terms of the consequences of disease for health, and it defends the wider efforts to measure health by those who are in other ways skeptical of the project of measuring the GBD. PMID:22852827

  20. [Viral safety: European and French directives].

    PubMed

    Rossi, F; Legras, J F

    2000-05-01

    The viral safety of IVIg is defined by transposition of European Directives. Directive 89/381/CEE defines plasma-derived medicinal products (pd-MP) which should be registred through a Marketing Authorization (75/318/CEE) and requires specific criteria for donation acceptability and fractionation processing. Recommendations and Notes for Guidance are prepared by the "Biotechnology Working Party" (BWP), Committee for Proprietary Medicinal Products (CPMP) ad hoc group. "Note for Guidance on Virus Validation Studies: CPMP/BWP/268/95" defines, for conventional viruses, the validation study as regards viral elimination /inactivation steps (relevant virus, scale reduction system and statistical interpretation of the results). "Note for Guidance on 'blood products'- CPMP/BWP/269/95" defines the key issues of viral safety: starting material, viral elimination /inactivation steps within the fractionation processing and in process controls. Pd-MP used as excipients are also covered. BWP/CPMP recommends that exclusion criteria only be considered for sporadic, familial or iatrogenic Creutzfeldt-Jakob disease (CJD), while withdrawal should be undertaken, according to the precaution principle, when a donor is suffering from nv-CJD (February 1998). Also, screening tests currently under development for transmissible spongiform encephalopathies are encouraged to be introduced for fractionation products (January 1999). Some donor exclusion criteria for conventional viruses and prions are specific to France. In conclusion, measures taken to ensure pd-MP viral safety are constantly changing. Its evaluation can only be done when considering numerous parameters within a global context.

  1. [Prions: where do we stand 20 years after the appearance of bovine spongiform encephalopathy?].

    PubMed

    Crozet, Carole; Lehmann, Sylvain

    2007-12-01

    Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) identified twenty years ago in the British cattle herds. Creutzfeldt-Jakob disease (CJD) is a TSE that occurs in humans. In 1996, scientists found a possible link between BSE and a new variant of CJD (vCJD). The fact that the non conventional infectious agent of TSE, named prions, could cross the species barrier from cattle to human through meat consumption, raised a tremendous concern for public safety in Europe. This led to the development in the following two decades of substantial and expensive measures to contain BSE and prevent its transmission to humans. In parallel, scientific programs have been funded to progress through the comprehension of the physiopathology of these fatal disorders. In Europe, the BSE epidemics is now ending and the number of cases is decreasing thanks to the strict control of animal foodstuff that was the main source of prion contamination. Only a small number of vCJD have been detected, however, additional concerns have been raised recently for public safety as secondary transmission of CJD through medical procedure and blood transfusion is possible. In addition, the possibility that the BSE was transmitted to other animals including small ruminants is also worrisome. Research efforts are now focussing on decontamination and ante mortem diagnosis of TSE to prevent animal and human transmission. However, needs for fundamental research are still important as many questions remain to be addressed to understand the mechanism of prion transmission, as well as its pathogenesis.

  2. Quantification of thymosin beta(4) in human cerebrospinal fluid using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

    PubMed

    Urso, Elena; Le Pera, Maria; Bossio, Sabrina; Sprovieri, Teresa; Qualtieri, Antonio

    2010-07-01

    Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) has been applied to the analysis of a wide range of biomolecules. To date, there are two specific areas of application where MALDI-TOF-MS is viewed as impractical: analysis of low-mass analytes and relative quantitative applications. However, these limitations can be overcome and quantification can be routine. Increased levels of thymosin beta(4) (TB4) have been recently found in cerebrospinal fluid (CSF) from Creutzfeldt-Jakob disease (CJD) patients. Our objective was to apply a label-free quantitative application of MALDI-TOF-MS to measure TB4 levels in human CSF by adding the oxidized form of TB4 as an internal standard. The relative peak area or peak height ratios of the native TB4 to the added oxidized form were evaluated. Considering the relative peak area ratios, healthy individuals showed a mean value of 40.8+/-21.27 ng/ml, whereas CJD patients showed high values with a mean of 154+/-59.07 ng/ml, in agreement with the previous observation found in CJD patients. Similar results were obtained considering peak height ratios. The proposed method may provide a simple and rapid screening method for quantification on CSF of TB4 levels suitable for diagnostic purposes. 2010 Elsevier Inc. All rights reserved.

  3. Measurement of renal function in patients with chronic kidney disease.

    PubMed

    Sandilands, Euan A; Dhaun, Neeraj; Dear, James W; Webb, David J

    2013-10-01

    Chronic kidney disease affects millions of people worldwide and is associated with an increased morbidity and mortality as a result of kidney failure and cardiovascular disease. Accurate assessment of kidney function is important in the clinical setting as a screening tool and for monitoring disease progression and guiding prognosis. In clinical research, the development of new methods to measure kidney function accurately is important in the search for new therapeutic targets and the discovery of novel biomarkers to aid early identification of kidney injury. This review considers different methods for measuring kidney function and their contribution to the improvement of detection, monitoring and treatment of chronic kidney disease.

  4. Measurement of renal function in patients with chronic kidney disease

    PubMed Central

    Sandilands, Euan A; Dhaun, Neeraj; Dear, James W; Webb, David J

    2013-01-01

    Chronic kidney disease affects millions of people worldwide and is associated with an increased morbidity and mortality as a result of kidney failure and cardiovascular disease. Accurate assessment of kidney function is important in the clinical setting as a screening tool and for monitoring disease progression and guiding prognosis. In clinical research, the development of new methods to measure kidney function accurately is important in the search for new therapeutic targets and the discovery of novel biomarkers to aid early identification of kidney injury. This review considers different methods for measuring kidney function and their contribution to the improvement of detection, monitoring and treatment of chronic kidney disease. PMID:23802624

  5. Kuru: A Journey Back in Time from Papua New Guinea to the Neanderthals’ Extinction

    PubMed Central

    Liberski, Pawel P.

    2013-01-01

    Kuru, the first human transmissible spongiform encephalopathy was transmitted to chimpanzees by D. Carleton Gajdusek (1923–2008). In this review, I briefly summarize the history of this seminal discovery along its epidemiology, clinical picture, neuropathology and molecular genetics. The discovery of kuru opened new windows into the realms of human medicine and was instrumental in the later transmission of Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease as well as the relevance that bovine spongiform encephalopathy had for transmission to humans. The transmission of kuru was one of the greatest contributions to biomedical sciences of the 20th century. PMID:25437203

  6. Kuru: the old epidemic in a new mirror.

    PubMed

    Goldfarb, Lev G

    2002-07-01

    The kuru epidemic lasted almost a century; it started in 1901-1902, reached epidemic proportions in the mid-1950s, and disappeared in the 1990s. Kuru is the prototype member of a group of disorders known as transmissible spongiform encephalopathies (TSEs) or prion diseases. Recent data on the genetics and pathogenesis of TSEs contribute to a better understanding of the documented kuru phenomena, and vice versa, observations made during the kuru epidemic are immensely helpful in understanding the epidemic of variant Creutzfeldt-Jakob disease that is currently developing in Europe. The major goal of this review is to identify and illustrate these points.

  7. Kuru: a journey back in time from papua new Guinea to the neanderthals' extinction.

    PubMed

    Liberski, Pawel P

    2013-07-18

    Kuru, the first human transmissible spongiform encephalopathy was transmitted to chimpanzees by D. Carleton Gajdusek (1923-2008). In this review, I briefly summarize the history of this seminal discovery along its epidemiology, clinical picture, neuropathology and molecular genetics. The discovery of kuru opened new windows into the realms of human medicine and was instrumental in the later transmission of Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease as well as the relevance that bovine spongiform encephalopathy had for transmission to humans. The transmission of kuru was one of the greatest contributions to biomedical sciences of the 20th century.

  8. Case Studies Illustrating Focal Alzheimer's, Fluent Aphasia, Late-Onset Memory Loss, and Rapid Dementia.

    PubMed

    Camsari, Gamze Balci; Murray, Melissa E; Graff-Radford, Neill R

    2016-08-01

    Many dementia subtypes have more shared signs and symptoms than defining ones. We review 8 cases with 4 overlapping syndromes and demonstrate how to distinguish the cases. These include focal cortical presentations of Alzheimer's disease (AD; posterior cortical atrophy and corticobasal syndrome [CBS]), fluent aphasia (semantic dementia and logopenic aphasia), late-onset slowly progressive dementia (hippocampal sclerosis and limbic predominant AD) and rapidly progressive dementia (Creutzfeldt-Jakob disease and limbic encephalitis). Recognizing the different syndromes can help the clinician to improve their diagnostic skills, leading to improved patient outcomes by early and accurate diagnosis, prompt treatment, and appropriate counseling and guidance. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Measures of Rheumatoid Arthritis Disease Activity in Australian Clinical Practice

    PubMed Central

    Taylor, Andrew; Bagga, Hanish

    2011-01-01

    Objectives. To investigate which rheumatoid arthritis (RA) disease activity measures are being collected in patients receiving glucocorticoids, non-biologic or biologic disease-modifying antirheumatic drugs (DMARDs) in Australian rheumatology practice. Methods. A retrospective audit of medical records was conducted from eight rheumatology practices around Australia. Each rheumatologist recruited 30 consecutive eligible patients into the review, 10 of whom must have been receiving a biological agent for rheumatoid arthritis. Disease activity measures and radiographic assessments were collected from each patient's last consultation. For biologic patients, disease activity measures were also collected from when the patient was first initiated on the biological agent. Results. At last consultation, the disease measures that were recorded most often were ESR (89.2%), haemoglobin (87.5%), and CRP (84.2%). DAS28 was infrequently recorded (16.3%). The rate of recording disease activity measures for patients receiving biologic DMARDs decreased over time (mean 27 months). Conclusion. This review has shown inconsistency of RA activity measures being recorded in Australian rheumatology clinical practice. An accurate assessment of the disease process is necessary to effectively target rheumatoid arthritis patients to treat in order to achieve optimal outcomes. PMID:22389794

  10. Kuru and D. Carleton Gajdusek: a close encounter.

    PubMed

    Liberski, Paweł P

    2009-01-01

    Kuru, the first human transmissible spongiform encephalopathy, was transmitted to chimpanzees by D. Carleton Gajdusek (1923-2008). In this review, I briefly summarize the history of this seminal discovery alongside its epidemiology, clinical picture, neuropathology and molecular genetics. The discovery of kuru opened new windows into the realms of human medicine and was instrumental in the later transmission of Creutzfeldt-Jakob disease as well as the prediction that bovine spongiform encephalopathy would be transmitted to humans. It was one of the greatest discoveries in biomedical sciences of the 20th century.

  11. Toward fluorescence detection of protein residues on surgical instruments

    NASA Astrophysics Data System (ADS)

    Richardson, Patricia R.; Jones, Anita C.; Baxter, Robert L.; Baxter, Helen C.; Whittaker, A. Gavin; Campbell, Gaynor A.

    2004-06-01

    Prion proteins are the infectious agents that cause Creutzfeldt-Jakob Disease (CJD) in humans. These proteins are particularly resistant to normal sterilization procedures, and the theoretical risk of prion transmission via surgical instruments is of current public and professional concern. We are currently investigating fluorescence methods for the detection of proteins on surfaces, with a view to developing an optical-fiber-based system for routine, online monitoring of residual protein contamination on surgical instruments, in hospital sterilization departments. This paper presents preliminary results on the detection of femtomole amounts of fluorescently labelled protein on surgical steel and discusses some of the problems involved in the detection of fluorescence from metal samples.

  12. Sexually transmitted diseases program performance measures: how are they performing?

    PubMed

    Peterman, Thomas A; Newman, Daniel R; Collins, Dayne E; Doshi, Sonal R; Berman, Stuart M

    2011-07-01

    Performance measures were developed in order to improve the performance of sexually transmitted disease (STD) prevention programs. A consultant worked with persons from STD programs and Centers for Disease Control and Prevention to identify possible measures. Measures were pilot tested for feasibility and relevance in several programs, then implemented nationwide in 2004. Data were collated and shared with programs and presented at national meetings. Site visits, webinars, and technical assistance focused on program improvement related to the measures. Reported data were analyzed to see if national performance improved on the activities measured. Some measures were dropped or revised, and quality of reported data improved over time. There was little evidence that overall program performance improved. Performance measures are one way to monitor performance, and might contribute to program improvement, but additional efforts are needed to improve performance.

  13. Wearable sensors objectively measure gait parameters in Parkinson's disease.

    PubMed

    Schlachetzki, Johannes C M; Barth, Jens; Marxreiter, Franz; Gossler, Julia; Kohl, Zacharias; Reinfelder, Samuel; Gassner, Heiko; Aminian, Kamiar; Eskofier, Bjoern M; Winkler, Jürgen; Klucken, Jochen

    2017-01-01

    Distinct gait characteristics like short steps and shuffling gait are prototypical signs commonly observed in Parkinson's disease. Routinely assessed by observation through clinicians, gait is rated as part of categorical clinical scores. There is an increasing need to provide quantitative measurements of gait, e.g. to provide detailed information about disease progression. Recently, we developed a wearable sensor-based gait analysis system as diagnostic tool that objectively assesses gait parameter in Parkinson's disease without the need of having a specialized gait laboratory. This system consists of inertial sensor units attached laterally to both shoes. The computed target of measures are spatiotemporal gait parameters including stride length and time, stance phase time, heel-strike and toe-off angle, toe clearance, and inter-stride variation from gait sequences. To translate this prototype into medical care, we conducted a cross-sectional study including 190 Parkinson's disease patients and 101 age-matched controls and measured gait characteristics during a 4x10 meter walk at the subjects' preferred speed. To determine intraindividual changes in gait, we monitored the gait characteristics of 63 patients longitudinally. Cross-sectional analysis revealed distinct spatiotemporal gait parameter differences reflecting typical Parkinson's disease gait characteristics including short steps, shuffling gait, and postural instability specific for different disease stages and levels of motor impairment. The longitudinal analysis revealed that gait parameters were sensitive to changes by mirroring the progressive nature of Parkinson's disease and corresponded to physician ratings. Taken together, we successfully show that wearable sensor-based gait analysis reaches clinical applicability providing a high biomechanical resolution for gait impairment in Parkinson's disease. These data demonstrate the feasibility and applicability of objective wearable sensor-based gait

  14. Prospective associations between measures of adiposity and periodontal disease.

    PubMed

    Jimenez, Monik; Hu, Frank B; Marino, Miguel; Li, Yi; Joshipura, Kaumudi J

    2012-08-01

    Obesity induced inflammation may promote periodontal tissue destruction and bone resorption inducing tooth loss. We examined the association between measures of adiposity and self-reported periodontal disease, using data from 36,910 healthy male participants of the Health Professionals Follow-Up Study (HPFS) who were free of periodontal disease at baseline and followed for ≤20 years (1986-2006). Self-reported height, weight, and periodontal disease data were collected at baseline, weight and periodontal disease were additionally collected on biennial follow-up questionnaires and waist and hip circumference were self-reported in 1987. These self-reported measures have been previously validated. The multivariable adjusted associations between BMI (kg/m(2)), waist circumference (WC), waist-to-hip ratio (WHR), and first report of periodontal disease diagnosis were evaluated using time-varying Cox models. We observed 2,979 new periodontal disease diagnoses during 596,561 person-years of follow-up. Significant associations and trends were observed between all measures of adiposity and periodontal disease after adjusting for age, smoking, race, dental profession, physical activity, fruit and vegetable intake, alcohol consumption, and diabetes status at baseline. BMI ≥30 kg/m(2) compared to BMI 18.5-24.9 kg/m(2) was significantly associated with greater risk of periodontal disease (hazard ratios (HR) = 1.30; 95% confidence interval (CI): 1.17-1.45). Elevated WC and WHR were significantly associated with a greater risk of periodontal disease (HR for extreme quintiles: WC = 1.27, 95% CI: 1.11-1.46; WHR = 1.34, 95% CI: 1.17-1.54). The associations of BMI and WC were significant even among nondiabetics and never smokers. Given the high prevalence of overweight, obesity, and periodontal disease this association may be of substantial public health importance.

  15. Infectious diseases following natural disasters: prevention and control measures.

    PubMed

    Kouadio, Isidore K; Aljunid, Syed; Kamigaki, Taro; Hammad, Karen; Oshitani, Hitoshi

    2012-01-01

    Natural disasters may lead to infectious disease outbreaks when they result in substantial population displacement and exacerbate synergic risk factors (change in the environment, in human conditions and in the vulnerability to existing pathogens) for disease transmission. We reviewed risk factors and potential infectious diseases resulting from prolonged secondary effects of major natural disasters that occurred from 2000 to 2011. Natural disasters including floods, tsunamis, earthquakes, tropical cyclones (e.g., hurricanes and typhoons) and tornadoes have been secondarily described with the following infectious diseases including diarrheal diseases, acute respiratory infections, malaria, leptospirosis, measles, dengue fever, viral hepatitis, typhoid fever, meningitis, as well as tetanus and cutaneous mucormycosis. Risk assessment is essential in post-disaster situations and the rapid implementation of control measures through re-establishment and improvement of primary healthcare delivery should be given high priority, especially in the absence of pre-disaster surveillance data.

  16. Patient satisfaction measurement in the disease management industry.

    PubMed

    Sen, Shaikat; Fawson, Paul; Cherrington, Graham; Douglas, Kathleen; Friedman, Neal; Maljanian, Rose; Fitzner, Karen; Tang, Pei; Soper, Steven; Wood, Steven

    2005-10-01

    In mid-2004, the Disease Management Association of America (DMAA) Patient Satisfaction Workgroup in association with J.D. Power and Associates (JDPA) conducted a literature review and a member survey to gain an understanding of the nature of patient satisfaction measurement as it pertains to disease management (DM) programs within the DM industry. A review of the relevant literature indicates that perhaps, with the exception of diabetes disease management, there are no prevalent, systematic, or statistically validated approaches for measuring patient satisfaction within the disease management industry. Most existing studies tend to focus on the effectiveness of a disease management program on clinical outcomes, with patient satisfaction measured only as a part of a battery of "outcome" measures. However, many of these studies do find positive associations between patient satisfaction and clinical outcomes. A majority of the 49 respondents who completed the member feedback survey hold relatively high positions in their organizations. The vast majority of respondents indicate their organizations conduct patient satisfaction surveys that assess overall satisfaction, satisfaction with materials and information provided, and with staff members. Patient satisfaction surveys are most common among the five common chronic diseases: diabetes, asthma, congestive heart failure (CHF), coronary artery disease (CAD), and chronic obstructive pulmonary disease (COPD). More than three in four respondents agree that patient satisfaction measurement is important to the long-term success of their programs. Respondents also indicate that along with intelligence on patients' overall satisfaction with the program, they would also like to gain an understanding of whether or not their programs actually help manage the patient's medical condition. Eight survey instruments currently in use and submitted by study participants were also reviewed. Most of these instruments are relatively short

  17. Topological Measurements of DWI Tractography for Alzheimer's Disease Detection

    PubMed Central

    Monaco, Alfonso; Neuroimaging Initiative, Alzheimer's Disease

    2017-01-01

    Neurodegenerative diseases affect brain morphology and connectivity, making complex networks a suitable tool to investigate and model their effects. Because of its stereotyped pattern Alzheimer's disease (AD) is a natural benchmark for the study of novel methodologies. Several studies have investigated the network centrality and segregation changes induced by AD, especially with a single subject approach. In this work, a holistic perspective based on the application of multiplex network concepts is introduced. We define and assess a diagnostic score to characterize the brain topology and measure the disease effects on a mixed cohort of 52 normal controls (NC) and 47 AD patients, from Alzheimer's Disease Neuroimaging Initiative (ADNI). The proposed topological score allows an accurate NC-AD classification: the average area under the curve (AUC) is 95% and the 95% confidence interval is 92%–99%. Besides, the combination of topological information and structural measures, such as the hippocampal volumes, was also investigated. Topology is able to capture the disease signature of AD and, as the methodology is general, it can find interesting applications to enhance our insight into disease with more heterogeneous patterns. PMID:28352290

  18. Kuru: its ramifications after fifty years.

    PubMed

    Liberski, P P; Brown, P

    2009-01-01

    Kuru was the first human neurodegenerative disease in the group of transmissible spongiform encephalopathies, prion diseases or, in the past, slow unconventional virus diseases. It was reported to Western medicine in 1957 by Gajdusek and Zigas. Kuru was spread by endocannibalism and because of this the ratio of affected women and children to men was excessive. The hallmark of kuru neuropathology is the amyloid plaque. We may speculate what would happen if kuru had not been discovered or did not exist. The infectious nature of Creutzfeldt-Jakob disease (CJD) would probably not have been suspected until the beginning of the variant CJD (vCJD) outbreak in the UK. Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease would have remained for decades as obscure neurodegenerations of merely academic interest. The familial forms of CJD would not have benefited from PRNP gene (a gene encoding for prion protein) analysis, but only later would have been studied by linkage analysis and reverse genetics probably. The study of kuru would have probably been of minimal interest to veterinarians and anthropologists until the bovine spongiform encephalopathy (BSE) epidemic began to exert its devastating effect. The discovery of vCJD would have been delayed, as no surveillance would have been initiated for CJD. And perhaps most importantly, the realization of 'protein-misfolding diseases', including not only the neurodegenerative but also an increasing number of non-neurological disorders, would have been delayed by decades.

  19. Measuring disparities in the incidence of sexually transmitted diseases.

    PubMed

    Hoover, Karen; Bohm, Michele; Keppel, Kenneth

    2008-12-01

    The Centers for Disease Control and Prevention (CDC) defines a health disparity as a "[health] difference that occurs by gender, race or ethnicity, education or income, disability, geographic location, or sexual orientation." Health equity is achieved by eliminating health disparities or inequalities. Measuring health disparities is a critical first step toward reducing differences in health outcomes. To determine the methods to be used in measuring a health disparity, several decisions must be made, which include: (1) selecting a reference group for the comparison of 2 or more groups; (2) determining whether a disparity should be measured in absolute or in relative terms; (3) opting to measure health outcomes or health indicators expressed as adverse or favorable events; (4) selecting a method to monitor a disparity over time; and (5) choosing to measure a disparity as a pair-wise comparison between 2 groups or in terms of a summary measure of disparity among all groups for a particular characteristic. Different choices may lead to different conclusions about the size and direction of health disparities at a point in time and changes in disparities over time.The objective of this article is to review the methods for measuring health disparities, provide examples of their use, and make specific recommendations for measuring disparities in the incidence of sexually transmitted diseases (STDs).

  20. The role of disease burden measures in future estimates of endemic waterborne disease.

    PubMed

    Rice, Glenn; Heberling, Matthew T; Rothermich, Mary; Wright, J Michael; Murphy, Patricia A; Craun, Michael F; Craun, Gunther F

    2006-01-01

    The 1996 Safe Drinking Water Act amendments require the US Environmental Protection Agency and the Centers for Disease Control and Prevention to develop a national estimate of the occurrence of waterborne infectious disease that is attributable to public drinking water systems in the United States. Much of the information for developing the national estimate will be derived from epidemiologic data, and the primary outcome of this effort will be an estimate of the number of cases of gastrointestinal illness. While quantifying the number of these cases provides some measure of waterborne disease impact, the usefulness of this measure may be limited because the full spectrum of societal impact also involves consideration of the additional effects of these diseases such as hospitalization costs and lost productivity. If decision-makers wish to compare the impact of waterborne infectious diseases to the impact of some other public health concern (e.g. to aid in resource allocation decisions), then a comparison of case numbers may prove inadequate. Case numbers alone do not provide sufficient information about the severity of different illnesses. Society may value the avoidance of a few cases of severely debilitating illness more than it values the avoidance of many cases of mild illness. In order to compare disparate public health concerns, "burden of disease" measures that incorporate indicators of disease severity, costs, or societal values may prove essential for some types of decisions. We describe epidemiologic measures of severity, quality adjusted life years (QALYs), disability adjusted life years (DALYs), willingness-to-pay, and cost-of-illness methods commonly used for burden of disease estimates, and discuss how some of these summary measures of burden might be used for waterborne disease estimates.

  1. Quality improvement in neurology: AAN Parkinson disease quality measures

    PubMed Central

    Cheng, E.M.; Tonn, S.; Swain-Eng, R.; Factor, S.A.; Weiner, W.J.; Bever, C.T.

    2010-01-01

    Background: Measuring the quality of health care is a fundamental step toward improving health care and is increasingly used in pay-for-performance initiatives and maintenance of certification requirements. Measure development to date has focused on primary care and common conditions such as diabetes; thus, the number of measures that apply to neurologic care is limited. The American Academy of Neurology (AAN) identified the need for neurologists to develop measures of neurologic care and to establish a process to accomplish this. Objective: To adapt and test the feasibility of a process for independent development by the AAN of measures for neurologic conditions for national measurement programs. Methods: A process that has been used nationally for measure development was adapted for use by the AAN. Topics for measure development are chosen based upon national priorities, available evidence base from a systematic literature search, gaps in care, and the potential impact for quality improvement. A panel composed of subject matter and measure development methodology experts oversees the development of the measures. Recommendation statements and their corresponding level of evidence are reviewed and considered for development into draft candidate measures. The candidate measures are refined by the expert panel during a 30-day public comment period and by review by the American Medical Association for Current Procedural Terminology (CPT) II codes. All final AAN measures are approved by the AAN Board of Directors. Results: Parkinson disease (PD) was chosen for measure development. A review of the medical literature identified 258 relevant recommendation statements. A 28-member panel approved 10 quality measures for PD that included full specifications and CPT II codes. Conclusion: The AAN has adapted a measure development process that is suitable for national measurement programs and has demonstrated its capability to independently develop quality measures. GLOSSARY

  2. Measurement of the area of involvement in skin disease

    NASA Astrophysics Data System (ADS)

    Roening, Juha; Kontinen, Jukka

    1996-10-01

    The ability to assess the severity of dermatoses by measuring the area of involvement is important in both clinical practice and research, but it has been shown that physicians, nurses and other groups are unable to do this accurately. A common practice in current use is the 'rule of nine' method, but wide variations have been found between observers' estimates. The purpose of this work was to test and demonstrate the feasibility of a computer vision technique for measuring the area of involvement in skin diseases by developing a system for psoriasis area assessment form slides, which can be operated in an image processing environment. The exact percentage of the slide area involved varied from 1 percent to 59 percent, thus providing realistic material for the system. The system proved sufficiently accurate, and the techniques evidently have a potential for inclusion as parts of a more accurate and rapid method for area measurement in the case of skin diseases.

  3. The Canadian Management of Bovine Spongiform Encephalopathy in Historical and Scientific Perspective, 1990-2014.

    PubMed

    Quimby, Alexandra E; Shamy, Michel C F

    2015-11-01

    On February 11, 2015, the Canadian Food Inspection Agency announced that a cow born and raised in Alberta had tested positive for bovine spongiform encephalopathy (BSE), commonly known as mad cow disease. BSE is a prion disease of cattle that, when transmitted to humans, produces a fatal neurodegenerative disease known as variant Creutzfeldt-Jakob disease. We believe that this latest case of BSE in Canadian cattle suggests the timeliness of a review of the management of BSE in Canada from a historically and scientifically informed perspective. In this article, we ask: how did the Canadian management of BSE between 1990 and 2014 engage with the contemporary understanding of BSE's human health implications? We propose that Canadian policies largely ignored the implicit medical nature of BSE, treating it as a purely agricultural and veterinary issue. In this way, policies to protect Canadians were often delayed and incomplete, in a manner disturbingly reminiscent of Britain's failed management of BSE. Despite assurances to the contrary, it is premature to conclude that BSE (and with it the risk of variant Creutzfeldt-Jakob disease) is a thing of Canada's past: BSE remains very much an issue in Canada's present.

  4. Sonographic evaluation of pediatric localized scleroderma: preliminary disease assessment measures

    PubMed Central

    2010-01-01

    Background Our earlier work in the ultrasonograpy of localized scleroderma (LS) suggests that altered levels of echogenicity and vascularity can be associated with disease activity. Utrasound is clinically benign and readily available, but can be limited by operator dependence. We present our efforts to standardize image acquisition and interpretation of pediatric LS to better evaluate the correlation between specific sonographic findings and disease activity. Methods Several meetings have been held among our multi-center group (LOCUS) to work towards standardizing sonographic technique and image interpretation. Demonstration and experience in image acquisition were conducted at workshop meetings. Following meetings in 2007, an ultrasound measure was developed to standardize evaluation of differences in echogenicity and vascularity. Based upon our initial observations, we have labeled this an ultrasound disease activity measure. This preliminary measure was subsequently evaluated on over 180 scans of pediatric LS lesions. This review suggested that scoring levels should be expanded to better capture the range of observed differences. The revised levels and their definitions were formulated at a February 2009 workshop meeting. We have also developed assessments for scoring changes in tissue thickness and lesion size to better determine if these parameters aid evaluation of disease state. Results We have standardized our protocol for acquiring ultrasound images of pediatric LS lesions. A wide range of sonographic differences has been seen in the dermis, hypodermis, and deep tissue layers of active lesions. Preliminary ultrasound assessments have been generated. The disease activity measure scores for altered levels of echogenicity and vascularity in the lesion, and other assessments score for differences in lesion tissue layer thickness and changes in lesion size. Conclusions We describe the range of sonographic differences found in pediatric LS, and present our

  5. Kuru: Genes, Cannibals and Neuropathology

    PubMed Central

    Liberski, Pawel P.; Sikorska, Beata; Lindenbaum, Shirley; Goldfarb, Lev G.; McLean, Catriona; Hainfellner, Johannes A.; Brown, Paul

    2016-01-01

    Kuru was the first human transmissible spongiform encephalopathy (TSE) or prion disease identified, occurring in the Fore linguistic group of Papua New Guinea. Kuru was a uniformly fatal cerebellar ataxic syndrome, usually followed by choreiform and athetoid movements. Kuru imposed a strong balancing selection on the Fore population, with individuals homozygous for the 129 Met allele of the gene (PRNP) encoding for prion protein (PrP) being the most susceptible. The decline in the incidence of kuru in the Fore has been attributed to the exhaustion of the susceptible genotype and ultimately by discontinuation of exposure via cannibalism. Neuropathologically, kuru-affected brains were characterized by widespread degeneration of neurons, astroglial and microglial proliferation, and the presence of amyloid plaques. These early findings have been confirmed and extended by recent immunohistochemical studies for the detection of the TSE-specific PrP (PrPTSE). Confocal laser microscopy also showed the concentration of glial fibrillary acidic protein–positive astrocytic processes at the plaque periphery. The fine structure of plaques corresponds to that described earlier by light microscopy. The successful experimental transmission of kuru led to the awareness of its similarity to Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease and formed a background against which the recent epidemics of iatrogenic and variant Creutzfeldt-Jakob disease could be studied. PMID:22249461

  6. Kuru: genes, cannibals and neuropathology.

    PubMed

    Liberski, Pawel P; Sikorska, Beata; Lindenbaum, Shirley; Goldfarb, Lev G; McLean, Catriona; Hainfellner, Johannes A; Brown, Paul

    2012-02-01

    Kuru was the first human transmissible spongiform encephalopathy (TSE) or prion disease identified, occurring in the Fore linguistic group of Papua New Guinea. Kuru was a uniformly fatal cerebellar ataxic syndrome, usually followed by choreiform and athetoid movements. Kuru imposed a strong balancing selection on the Fore population, with individuals homozygous for the 129 Met allele of the gene (PRNP) encoding for prion protein (PrP) being the most susceptible. The decline in the incidence of kuru in the Fore has been attributed to the exhaustion of the susceptible genotype and ultimately by discontinuation of exposure via cannibalism. Neuropathologically, kuru-affected brains were characterized by widespread degeneration of neurons, astroglial and microglial proliferation, and the presence of amyloid plaques. These early findings have been confirmed and extended by recent immunohistochemical studies for the detection of the TSE-specific PrP (PrP). Confocal laser microscopy also showed the concentration of glial fibrillary acidic protein-positive astrocytic processes at the plaque periphery. The fine structure of plaques corresponds to that described earlier by light microscopy. The successful experimental transmission of kuru led to the awareness of its similarity to Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease and formed a background against which the recent epidemics of iatrogenic and variant Creutzfeldt-Jakob disease could be studied.

  7. Measuring Ankle Instability in Pediatric Charcot-Marie-Tooth Disease.

    PubMed

    Mandarakas, Melissa; Hiller, Claire E; Rose, Kristy J; Burns, Joshua

    2013-11-01

    Children with Charcot-Marie-Tooth disease frequently suffer ankle sprain and experience chronic ankle instability; however, no pediatric self-reported measures of chronic ankle instability exist. The aim was to modify and validate the most reliable measure of chronic ankle instability in adults: the Cumberland Ankle Instability Tool. The Cumberland Ankle Instability Tool-Youth was tested for reliability, construct validity, and sensitivity to discriminate between 104 children aged 8 to 16 years: 31 children with Charcot-Marie-Tooth disease, 31 unaffected children with a history of ankle sprains, and 42 controls. Children with Charcot-Marie-Tooth disease had lower scores compared to unaffected children with a history of sprains (χ(2) = 15.10; P < .001) and controls (χ(2) = 33.69; P < .001). Scores moderately correlated to visual analog scale scores of ankle steadiness (r s = 0.684; P < .001), and "good" test-retest reliability was identified (ICC2,1 = 0.73). The Cumberland Ankle Instability Tool-Youth demonstrated excellent sensitivity and construct validity, identifying chronic ankle instability as a common problem for children with Charcot-Marie-Tooth disease.

  8. TRACTOGRAPHY DENSITY AND NETWORK MEASURES IN ALZHEIMER'S DISEASE.

    PubMed

    Prasad, Gautam; Nir, Talia M; Toga, Arthur W; Thompson, Paul M

    2013-04-01