BACKGROUND Prion diseases are a group of degenerative nerve diseases that are caused by infectious prion proteins or gene mutations.In humans,prion diseases result from mutations in the prion protein gene(PRNP).Only a...BACKGROUND Prion diseases are a group of degenerative nerve diseases that are caused by infectious prion proteins or gene mutations.In humans,prion diseases result from mutations in the prion protein gene(PRNP).Only a limited number of cases involving a specific PRNP mutation at codon 196(E196A)have been reported.The coexistence of Korsakoff syndrome in patients with Creutzfeldt-Jakob disease(CJD)caused by E196A mutation has not been documented in the existing literature.CASE SUMMARY A 61-year-old Chinese man initially presented with Korsakoff syndrome,followed by rapid-onset dementia,visual hallucinations,akinetic mutism,myoclonus,and hyperthermia.The patient had no significant personal or familial medical history.Magnetic resonance imaging of the brain revealed extensive hyperintense signals in the cortex,while positron emission tomography/computed tomography showed a diffuse reduction in cerebral cortex metabolism.Routine biochemical and microorganism testing of the cerebrospinal fluid(CSF)yielded normal results.Tests for thyroid function,human immunodeficiency virus,syphilis,vitamin B1 and B12 levels,and autoimmune rheumatic disorders were normal.Blood and CSF tests for autoimmune encephalitis and autoantibody-associated paraneoplastic syndrome yielded negative results.A test for 14-3-3 protein in the CSF yielded negative results.Whole-genome sequencing revealed a diseasecausing mutation in PRNP.The patient succumbed to the illness 11 months after the initial symptom onset.CONCLUSION Korsakoff syndrome,typically associated with alcohol intoxication,also manifests in CJD patients.Individuals with CJD along with PRNP E196A mutation may present with Korsakoff syndrome.展开更多
Prion diseases are infectious protein misfolding disorders of the central nervous system that result from misfolding of the cellular prion protein(PrPC)into the pathologic isoform PrPSc.Pathologic hallmarks of prion d...Prion diseases are infectious protein misfolding disorders of the central nervous system that result from misfolding of the cellular prion protein(PrPC)into the pathologic isoform PrPSc.Pathologic hallmarks of prion disease are depositions of pathological prion protein PrPSc,neuronal loss,spongiform degeneration and astrogliosis in the brain.Prion diseases affect human and animals,there is no effective therapy,and they invariably remain fatal.For a long time,neuronal loss was considered the sole reason for neurodegeneration in prion pathogenesis,and the contribution of non-neuronal cells like microglia and astrocytes was considered less important.Recent evidence suggests that neurodegeneration during prion pathogenesis is a consequence of a complex interplay between neuronal and non-neuronal cells in the brain,but the exact role of these non-neuronal cells during prion pathology is still elusive.Astrocytes are non-neuronal cells that regulate brain homeostasis under physiological conditions.However,astrocytes can deposit PrPSc aggregates and propagate prions in prion-infected brains.Additionally,sub-populations of reactive astrocytes that include neurotrophic and neurotoxic species have been identified,differentially expressed in the brain during prion infection.Revealing the exact role of astrocytes in prion disease is hampered by the lack of in vitro models of prion-infected astrocytes.Recently,we established a murine astrocyte cell line persistently infected with mouse-adapted prions,and showed how such astrocytes differentially process various prion strains.Considering the complexity of the role of astrocytes in prion pathogenesis,we need more in vitro and in vivo models for exploring the contribution of sub-populations of reactive astrocytes,their differential regulation of signaling cascades,and the interaction with neurons and microglia during prion pathogenesis.This will help to establish novel in vivo models and define new therapeutic targets against prion diseases.In this review,we will discuss the complex role of astrocytes in prion disease,the existing experimental resources,the challenges to analyze the contribution of astrocytes in prion disease pathogenesis,and future strategies to improve the understanding of their role in prion disease.展开更多
Human prion disease is a rare,uniformly fatal neurodegenerative disorder.Its precise pathogenesis is obscure.The clinical profile of the disease differs among its various forms.There are no definitive diagnostic tests...Human prion disease is a rare,uniformly fatal neurodegenerative disorder.Its precise pathogenesis is obscure.The clinical profile of the disease differs among its various forms.There are no definitive diagnostic tests(except for brain biopsy)or proven treatment.To increase the clinical diagnostic sensitivity and specificity,three laboratory tests,including electroencephalogram,cerebrospinal fluid testing for 14-3-3 protein,and magnetic resonance imaging,are currently used.Additionally,proton magnetic resonance spectroscopy,positron emission tomography and single photon emission computed tomography can provide interesting and novel results in the research of human prion disease.展开更多
BACKGROUND Creutzfeldt-Jakob disease(CJD)is a rare degenerative disease of the central nervous system that can be contagious or hereditary and is a rare cause of rapidly progressive dementia.It almost always results i...BACKGROUND Creutzfeldt-Jakob disease(CJD)is a rare degenerative disease of the central nervous system that can be contagious or hereditary and is a rare cause of rapidly progressive dementia.It almost always results in death within 1-2 years from symptom onset.CASE SUMMARY Here,we report the case of a 57-year-old male who initially experienced dizziness followed by a 1-mo fast decline in memory function.He presented to the local hospital and underwent magnetic resonance imaging and cerebrospinal fluid(CSF)examination,with no definitive diagnosis.However,the symptoms of progressive forgetting worsened.In addition,he exhibited progressive involuntary tremor of the limbs.Then,he came to our hospital,and according to the results of CSF examination,electroencephalography(EEG)and magnetic resonance imaging(MRI)tests and clinical manifestations of cerebellar ataxia,dementia,and myoclonus that rapidly progressed,with a short duration of illness,he was finally diagnosed with sporadic CJD(sCJD).CONCLUSION This case report aims to create awareness among physicians to emphasize auxiliary examination,CSF examination,EEG and MRI tests and recognition of cerebellar ataxia,dementia,and myoclonus that rapidly progress to prompt pursuit of an early diagnosis and identification of sCJD and to reduce complications.展开更多
Creuzfelt-Jakob Disease is a rare and progressive neurodegenerative disease that results in fatal, transmissible, subacute, spongiform encephalopathy characterized by rapidly progressive dementia and movement disorder...Creuzfelt-Jakob Disease is a rare and progressive neurodegenerative disease that results in fatal, transmissible, subacute, spongiform encephalopathy characterized by rapidly progressive dementia and movement disorder. We present a 62-year-old male with no medical history who was admitted to our hospital because of gait and balance disturbance, language impairment and progressive motor deficit of the four limbs. A neurological examination found frontal lobe syndrome signs, myoclonic movements, pyramidal and extra-pyramidal signs. Brain Magnetic Resonance Imaging detected high intensity areas in the basal ganglia. EEG showed generalized triphasic sharp-wave complexes. A Cerebro Spinal Fluid examination found protein 14-3-3. Death occurred six months after onset. This is the first known case of Creuzfelt-Jakob Disease documented in Senegal.展开更多
Human genetic prion diseases(gPrDs)are directly associated with mutations and insertions in the PRNP(Prion Protein)gene.We collected and analyzed the data of 218 Chinese gPrD patients identified between Jan 2006 and J...Human genetic prion diseases(gPrDs)are directly associated with mutations and insertions in the PRNP(Prion Protein)gene.We collected and analyzed the data of 218 Chinese gPrD patients identified between Jan 2006 and June 2020.Nineteen different subtypes were identified and gPrDs accounted for 10.9%of all diagnosed PrDs within the same period.Some subtypes of gPrDs showed a degree of geographic association.The age at onset of Chinese gPrDs peaked in the 50–59 year group.Gerstmann–Sträussler–Scheinker syndrome(GSS)and fatal familial insomnia(FFI)cases usually displayed clinical symptoms earlier than genetic Creutzfeldt–Jakob disease(gCJD)patients with point mutations.A family history was more frequently recalled in P105L GSS and D178N FFI patients than T188K and E200K patients.None of the E196A gCJD patients reported a family history.The gCJD cases with point mutations always developed clinical manifestations typical of sporadic CJD(sCJD).EEG examination was not sensitive for gPrDs.sCJD-associated abnormalities on MRI were found in high proportions of GSS and gCJD patients.CSF 14-3-3 positivity was frequently detected in gCJD patients.Increased CSF tau was found in more than half of FFI and T188K gCJD cases,and an even higher proportion of E196A and E200K gCJD patients.63.6%of P105L GSS cases showed a positive reaction in cerebrospinal fluid RT-QuIC.GSS and FFI cases had longer durations than most subtypes of gCJD.This is one of the largest studies of gPrDs in East Asians,and the illness profile of Chinese gPrDs is clearly distinct.Extremely high proportions of T188K and E196A occur among Chinese gPrDs;these mutations are rarely reported in Caucasians and Japanese.展开更多
Human prion diseases are a group of transmissible,progressive,and invariably fatal neurodegenerative disorders,which include Kuru,Creutzfeldt-Jakob disease(CJD),Gerstmann-Sträussler-Scheinker syndrome,and fatal f...Human prion diseases are a group of transmissible,progressive,and invariably fatal neurodegenerative disorders,which include Kuru,Creutzfeldt-Jakob disease(CJD),Gerstmann-Sträussler-Scheinker syndrome,and fatal familial insomnia.Human prion diseases affect approximately 1–2 persons per million worldwide annually,occurring in sporadic,inherited,and acquired forms.These diseases have attracted both scientific and public attention not only because of their mysterious pathogen,but also due to their considerable threat to public health since the emergence of the variant CJD.There are still no specific therapeutic and prophylactic interventions available for prion diseases,thus active surveillance of human prion diseases is critical for disease control and prevention.Since 1993,CJD surveillance systems have been established in many countries and regions,and several long-term multinational cooperative projects have been conducted.In this paper,the epidemiological characteristics of various human prion diseases and the active surveillance systems pertaining to them in different countries and regions are summarized and reviewed.展开更多
In prion diseases the irreversible protein structural transformation process is completed in the brains of mammals within a few months, the uniformly generated infectivity displays extraordinary resistance to inactiva...In prion diseases the irreversible protein structural transformation process is completed in the brains of mammals within a few months, the uniformly generated infectivity displays extraordinary resistance to inactivation, suggesting that a vital energy source is required for the production of infectious particles. Considering the high oxygen-respiration rate in the brains, prion protein oxidative damage can be the crucial factor. Both theoretical consideration of the nature of protein radical reactions and a large body of previously unraveled feature of scrapie and prion diseases have provided multiple distinct lines of compelling evidence which persuasively support a suggestion that the infectious agents may be prion (free) radicals produced from protein oxidative damage. This paper describes that scrapie prions are most likely formed from prion radicals and oxidative species-mediated sequence-specific cross-linking of benign prion proteins.展开更多
文摘BACKGROUND Prion diseases are a group of degenerative nerve diseases that are caused by infectious prion proteins or gene mutations.In humans,prion diseases result from mutations in the prion protein gene(PRNP).Only a limited number of cases involving a specific PRNP mutation at codon 196(E196A)have been reported.The coexistence of Korsakoff syndrome in patients with Creutzfeldt-Jakob disease(CJD)caused by E196A mutation has not been documented in the existing literature.CASE SUMMARY A 61-year-old Chinese man initially presented with Korsakoff syndrome,followed by rapid-onset dementia,visual hallucinations,akinetic mutism,myoclonus,and hyperthermia.The patient had no significant personal or familial medical history.Magnetic resonance imaging of the brain revealed extensive hyperintense signals in the cortex,while positron emission tomography/computed tomography showed a diffuse reduction in cerebral cortex metabolism.Routine biochemical and microorganism testing of the cerebrospinal fluid(CSF)yielded normal results.Tests for thyroid function,human immunodeficiency virus,syphilis,vitamin B1 and B12 levels,and autoimmune rheumatic disorders were normal.Blood and CSF tests for autoimmune encephalitis and autoantibody-associated paraneoplastic syndrome yielded negative results.A test for 14-3-3 protein in the CSF yielded negative results.Whole-genome sequencing revealed a diseasecausing mutation in PRNP.The patient succumbed to the illness 11 months after the initial symptom onset.CONCLUSION Korsakoff syndrome,typically associated with alcohol intoxication,also manifests in CJD patients.Individuals with CJD along with PRNP E196A mutation may present with Korsakoff syndrome.
基金supported by grants from Alberta Innovates/Alberta Prion Research Institute(APRI grants 201600010 and 201900008)(to HMS)ST had received a University of Calgary Eyes High,Killam and Alberta Innovates Health Solution(AIHS)doctoral fellowship.
文摘Prion diseases are infectious protein misfolding disorders of the central nervous system that result from misfolding of the cellular prion protein(PrPC)into the pathologic isoform PrPSc.Pathologic hallmarks of prion disease are depositions of pathological prion protein PrPSc,neuronal loss,spongiform degeneration and astrogliosis in the brain.Prion diseases affect human and animals,there is no effective therapy,and they invariably remain fatal.For a long time,neuronal loss was considered the sole reason for neurodegeneration in prion pathogenesis,and the contribution of non-neuronal cells like microglia and astrocytes was considered less important.Recent evidence suggests that neurodegeneration during prion pathogenesis is a consequence of a complex interplay between neuronal and non-neuronal cells in the brain,but the exact role of these non-neuronal cells during prion pathology is still elusive.Astrocytes are non-neuronal cells that regulate brain homeostasis under physiological conditions.However,astrocytes can deposit PrPSc aggregates and propagate prions in prion-infected brains.Additionally,sub-populations of reactive astrocytes that include neurotrophic and neurotoxic species have been identified,differentially expressed in the brain during prion infection.Revealing the exact role of astrocytes in prion disease is hampered by the lack of in vitro models of prion-infected astrocytes.Recently,we established a murine astrocyte cell line persistently infected with mouse-adapted prions,and showed how such astrocytes differentially process various prion strains.Considering the complexity of the role of astrocytes in prion pathogenesis,we need more in vitro and in vivo models for exploring the contribution of sub-populations of reactive astrocytes,their differential regulation of signaling cascades,and the interaction with neurons and microglia during prion pathogenesis.This will help to establish novel in vivo models and define new therapeutic targets against prion diseases.In this review,we will discuss the complex role of astrocytes in prion disease,the existing experimental resources,the challenges to analyze the contribution of astrocytes in prion disease pathogenesis,and future strategies to improve the understanding of their role in prion disease.
文摘Human prion disease is a rare,uniformly fatal neurodegenerative disorder.Its precise pathogenesis is obscure.The clinical profile of the disease differs among its various forms.There are no definitive diagnostic tests(except for brain biopsy)or proven treatment.To increase the clinical diagnostic sensitivity and specificity,three laboratory tests,including electroencephalogram,cerebrospinal fluid testing for 14-3-3 protein,and magnetic resonance imaging,are currently used.Additionally,proton magnetic resonance spectroscopy,positron emission tomography and single photon emission computed tomography can provide interesting and novel results in the research of human prion disease.
基金Shanghai Shenkang Hospital Development Center,No.SHDC12016109.
文摘BACKGROUND Creutzfeldt-Jakob disease(CJD)is a rare degenerative disease of the central nervous system that can be contagious or hereditary and is a rare cause of rapidly progressive dementia.It almost always results in death within 1-2 years from symptom onset.CASE SUMMARY Here,we report the case of a 57-year-old male who initially experienced dizziness followed by a 1-mo fast decline in memory function.He presented to the local hospital and underwent magnetic resonance imaging and cerebrospinal fluid(CSF)examination,with no definitive diagnosis.However,the symptoms of progressive forgetting worsened.In addition,he exhibited progressive involuntary tremor of the limbs.Then,he came to our hospital,and according to the results of CSF examination,electroencephalography(EEG)and magnetic resonance imaging(MRI)tests and clinical manifestations of cerebellar ataxia,dementia,and myoclonus that rapidly progressed,with a short duration of illness,he was finally diagnosed with sporadic CJD(sCJD).CONCLUSION This case report aims to create awareness among physicians to emphasize auxiliary examination,CSF examination,EEG and MRI tests and recognition of cerebellar ataxia,dementia,and myoclonus that rapidly progress to prompt pursuit of an early diagnosis and identification of sCJD and to reduce complications.
文摘Creuzfelt-Jakob Disease is a rare and progressive neurodegenerative disease that results in fatal, transmissible, subacute, spongiform encephalopathy characterized by rapidly progressive dementia and movement disorder. We present a 62-year-old male with no medical history who was admitted to our hospital because of gait and balance disturbance, language impairment and progressive motor deficit of the four limbs. A neurological examination found frontal lobe syndrome signs, myoclonic movements, pyramidal and extra-pyramidal signs. Brain Magnetic Resonance Imaging detected high intensity areas in the basal ganglia. EEG showed generalized triphasic sharp-wave complexes. A Cerebro Spinal Fluid examination found protein 14-3-3. Death occurred six months after onset. This is the first known case of Creuzfelt-Jakob Disease documented in Senegal.
基金This work was supported by the National Natural Science Foundation of China(81630062)the State Key Laboratory for Infectious Disease Prevention and Control,CDC,China(2019SKLID501,2019SKLID603,and 2019SKLID307).
文摘Human genetic prion diseases(gPrDs)are directly associated with mutations and insertions in the PRNP(Prion Protein)gene.We collected and analyzed the data of 218 Chinese gPrD patients identified between Jan 2006 and June 2020.Nineteen different subtypes were identified and gPrDs accounted for 10.9%of all diagnosed PrDs within the same period.Some subtypes of gPrDs showed a degree of geographic association.The age at onset of Chinese gPrDs peaked in the 50–59 year group.Gerstmann–Sträussler–Scheinker syndrome(GSS)and fatal familial insomnia(FFI)cases usually displayed clinical symptoms earlier than genetic Creutzfeldt–Jakob disease(gCJD)patients with point mutations.A family history was more frequently recalled in P105L GSS and D178N FFI patients than T188K and E200K patients.None of the E196A gCJD patients reported a family history.The gCJD cases with point mutations always developed clinical manifestations typical of sporadic CJD(sCJD).EEG examination was not sensitive for gPrDs.sCJD-associated abnormalities on MRI were found in high proportions of GSS and gCJD patients.CSF 14-3-3 positivity was frequently detected in gCJD patients.Increased CSF tau was found in more than half of FFI and T188K gCJD cases,and an even higher proportion of E196A and E200K gCJD patients.63.6%of P105L GSS cases showed a positive reaction in cerebrospinal fluid RT-QuIC.GSS and FFI cases had longer durations than most subtypes of gCJD.This is one of the largest studies of gPrDs in East Asians,and the illness profile of Chinese gPrDs is clearly distinct.Extremely high proportions of T188K and E196A occur among Chinese gPrDs;these mutations are rarely reported in Caucasians and Japanese.
基金supported by the Chinese National Natural Science Foundation Grants(81401670)the China Mega-Project for Infectious Diseases(2011ZX10004-101,2012ZX10004215)the SKLID Development Grant(2012SKLID102).
文摘Human prion diseases are a group of transmissible,progressive,and invariably fatal neurodegenerative disorders,which include Kuru,Creutzfeldt-Jakob disease(CJD),Gerstmann-Sträussler-Scheinker syndrome,and fatal familial insomnia.Human prion diseases affect approximately 1–2 persons per million worldwide annually,occurring in sporadic,inherited,and acquired forms.These diseases have attracted both scientific and public attention not only because of their mysterious pathogen,but also due to their considerable threat to public health since the emergence of the variant CJD.There are still no specific therapeutic and prophylactic interventions available for prion diseases,thus active surveillance of human prion diseases is critical for disease control and prevention.Since 1993,CJD surveillance systems have been established in many countries and regions,and several long-term multinational cooperative projects have been conducted.In this paper,the epidemiological characteristics of various human prion diseases and the active surveillance systems pertaining to them in different countries and regions are summarized and reviewed.
文摘In prion diseases the irreversible protein structural transformation process is completed in the brains of mammals within a few months, the uniformly generated infectivity displays extraordinary resistance to inactivation, suggesting that a vital energy source is required for the production of infectious particles. Considering the high oxygen-respiration rate in the brains, prion protein oxidative damage can be the crucial factor. Both theoretical consideration of the nature of protein radical reactions and a large body of previously unraveled feature of scrapie and prion diseases have provided multiple distinct lines of compelling evidence which persuasively support a suggestion that the infectious agents may be prion (free) radicals produced from protein oxidative damage. This paper describes that scrapie prions are most likely formed from prion radicals and oxidative species-mediated sequence-specific cross-linking of benign prion proteins.
