B115 牛海綿狀腦病(Bovine Spongiform Encephalopathy

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B115 牛海綿狀腦病(Bovine Spongiform Encephalopathy

  1. 1. Pathology of new variant Creutzfeldt-Jakob disease <ul><li>李進成 MD PhD </li></ul><ul><li>英國倫敦大學神經學研究所神經病理學博士 </li></ul><ul><li>新光醫院病理檢驗科主治醫師 </li></ul><ul><li>台北醫學大學及輔仁大學醫學院病理學科副教授 </li></ul>
  2. 2. Transmissible spongiform encephalopathies (TSE) <ul><li>Scrapie (綿羊搔癢症) 1700s </li></ul><ul><li>Transmissible mink encephalopathy (傳播性貂腦病) 1947 </li></ul><ul><li>Chronic wasting disease (慢性消耗性病) 1967 </li></ul><ul><li>Bovine spongiform encephalopathy (牛海綿狀腦病) 1986 </li></ul><ul><li>Zoo spongiform encephalopathy ( 野生動物海綿狀腦病) 1988 </li></ul><ul><li>Feline spongiform encephalopathy (貓海綿狀腦病) 1990 </li></ul><ul><li>Creutzfeldt-Jakob disease (CJD) (庫賈氏病) 1922 </li></ul><ul><li>Gerstamann-Sträussler-Scheinker disease 1936 </li></ul><ul><li>Kuru (庫魯病) 1957 </li></ul><ul><li>Fatal familial insomnia (致死性家族性失眠症) 1986 </li></ul><ul><li>Variant of CJD (變型庫賈氏病) 1994 </li></ul>
  3. 3. Prion (Creutzfeldt-Jakob) disease <ul><li>Prion (Creutzfeldt-Jakob) disease is a unique disorder that can occur in sporadic, acquired and familial forms. </li></ul><ul><li>It is characterized by the accumulation in the central nervous system (CNS) of an abnormally folded isoform of a host-encoded protein, which most consider the infectious agent. </li></ul><ul><li>The pathogenesis of the sporadic form of CJD is still poorly understood; instead, in the variant form (vCJD), the transmission from the bovine spongiform encephalopathy has been proven on biochemical, histopathological and epidemiologic grounds. </li></ul>
  4. 4. Characteristic features of TSE <ul><li>A group of degenerative neurological disorders causing behavioral changes, alterations of sensation, changes in mental state and ataxia </li></ul><ul><li>Non-inflammatory vacuolation (spongiosis) in neuronal perikarya and gray matter neuropil, neuronal cell loss, gliosis, and amyloid plaques </li></ul>
  5. 5. Characteristic features of TSE <ul><li>A long incubation period from many months to several decades </li></ul><ul><li>Transmitted as an infectious agent by inoculation or transmitted genetically to offspring following mutation of the “prion” (protein infectious organisms) protein ( prion-related protein ; PrP ) gene in a parent </li></ul>
  6. 6. 人類之 傳播性海綿狀腦病 <ul><li>庫賈氏病( Creutzfeldt-Jakob disease ; CJD ) </li></ul><ul><li>1922 年 : 庫氏( Creutzfeldt )報告 1 例 22 歲女性患有感覺、運動及精神問題 (not compatible with current definition of CJD). </li></ul><ul><li>賈氏( Jakob )報告 5 例 “僵直性假性硬化症 Spastic pseudosclerosis” ,其中有 2 例患者死亡後,經病理切片檢查,發現腦部灰質部有非炎症的海綿狀變化及神經細胞消失 (non-inflammatory spongiform change and neuronal loss). </li></ul><ul><li>當時認為這是一種神經退化性疾病 (neurodegenerative disease) 。 </li></ul>
  7. 7. Kuru 庫魯病 <ul><li>Gajdusek (1957) 年 至 新幾內亞 Papau New Guinea 東部高原的 Fore tribe 研究土著發生的神秘疾病。 </li></ul><ul><li>1966 年 Kuru 死亡病患之腦部切片與獸醫病理醫師哈德婁 (Hadlow) 討論後,得知其與綿羊搔癢症( Scrapie )的傳播性海綿狀腦病相當類似 </li></ul><ul><li>於是將庫魯病病患腦部抽出物接種於非人類靈長類動物,如黑猩猩等,而這些非人類靈長類也於 12~14 個月後出現與庫魯病病患類似的病症。證實庫魯病為一可傳播的疾病 (Transmissible disease) 。 </li></ul>
  8. 8. CJD-Transmissible <ul><li>加德賽克亦分別在 1968 年成功的將死於庫賈氏症 (Sporadic CJD) 及在 1981 年死於遺傳性庫賈氏症 (Familiar CJD) 病患腦部抽出物接種於非人類靈長類,而這些動物也於 1 年後出現與庫賈氏症病患相似的病症。 </li></ul><ul><li>當時他認為這是由於慢性病毒( slow virus, infectious amyloid )或非傳統病毒( unconventional virus )所引起。 </li></ul>
  9. 9. 傳染性蛋白粒子 prion (proteinaceous infectious particles) <ul><li>蒲希那( Prusiner )於 1982 年提出 prion 理論 , 認為傳播性海綿狀腦病是由一種具感染性的變性蛋白質 PrPsc (scrapie prion protein) 引起。 </li></ul><ul><li>它會將神經細胞內正常的蛋白質 PrPc (cellular prion protein) 加以轉變,而以等比級數的速度累積在神經細胞內,最後使腦組織形成海綿樣病變。 </li></ul>
  10. 10. S poradic CJD, clinical presentation <ul><li>Rapidly progressive mental deterioration with dementia, myoclonus, motor disturbances (pyramidal, extra-pyramidal, cerebellar, lower motor neurone) and periodic short-wave activity on EEG. 15% patients begin with ataxia (kuru-like).Following growth-hormone cerebellar symptoms and 6-18 months duration. </li></ul><ul><li>1 case/1 000 000/year, mean age 67; 95% over 50y. </li></ul>
  11. 11. Prion disease: CJD syndromes <ul><li>Showing vacuolation and no or little amyloid plaque formation. </li></ul><ul><li>Accounting for 90-95% of the total prion cases, >85% are sporadic. M/F=1.2/1. </li></ul><ul><li>In sporadic cases, no family history and no ‘infectious’ episode. Infectious and familial cases occur in younger patients. </li></ul><ul><li>Death in 4-12 mo, but occasionally 2-5 years. </li></ul>
  12. 12. Prion disease: pathology <ul><li>Three main features: </li></ul><ul><li>1) with vacuolar degeneration and little or no amyloid plaque formation: scrapie, BSE, sporadic, iatrogenic and familial CJD, sporadic and familial fatal insomnia; </li></ul><ul><li>2) abundant PrP amyloid plaque formation and variable vacuolar degeneration: GSS; kuru; </li></ul><ul><li>3) vacuolar changes and and abundant amyloid plaque formation (nvCJD). </li></ul>
  13. 13. Prion disease: neuropathology of sporadic CJD <ul><li>Gross appearance: from no abnormalities to variable degree of atrophy (including cerebellum). </li></ul><ul><li>Exceptionally very low brain weight (850 g recorded) </li></ul>
  14. 14. Prion disease: neuropathology of sporadic CJD <ul><li>Various subtypes: cortical; cortico-striatal with/without visual loss; cortico-striato-cerebellar; cortico-spinal; cortico-nigral. </li></ul><ul><li>Other sub-classifications are based on clinico-pathological criteria. </li></ul>
  15. 15. Prion disease: sporadic CJD <ul><li>In the most severe cases, vacuolation may become less apparent due to the loss of neurones and consequent collapse of the residual cortical structures </li></ul>
  16. 16. Prion disease: sporadic CJD: amyloid <ul><li>Amyloid plaques are present in 5-10% of the cases, most often in the cerebellar granule layer and resemble kuru plaques. They are PrP+ and βA4-. </li></ul><ul><li>Ultrastructurally amyloid consists of fibrils. </li></ul>
  17. 17. Prion diseases: familial forms <ul><li>They present at an earlier stage than sporadic cases. </li></ul><ul><li>Penetrance is close to 100%, but is age-dependant: for CJD it is 1% at 40 years, but close to 100% at 80. </li></ul><ul><li>This group includes: </li></ul><ul><li>1) Familial CJD and </li></ul><ul><li>2) Gerstmann-Str äussler-Scheinker forms </li></ul>
  18. 18. Gerstmann-Str äussler-Scheinker (GSS) syndrome <ul><li>Diagnosis includes dominant inheritance, cognitive and motor disturbances and widespread deposition of PrP amyloid plaques. </li></ul><ul><li>GSS includes six disorders. </li></ul><ul><li>Its incidence is 2-5 cases/100 million </li></ul>
  19. 19. GSS: Clinical presentation <ul><li>Onset in the 4 th -6 th decade; progression over 6 years. </li></ul><ul><li>Difficulty in walking, unsteadiness, paresthaesia, eventually mental and behavioural deterioration. </li></ul><ul><li>OE: cerebellar ataxia, dysarthria, ocular dysmetria, hyporreflexia and extensor plantars </li></ul>
  20. 20. GSS: Neuropathology <ul><li>The hallmark of the disorder is the presence of the multicentric plaque , most numerous in the cerebellar cortex, but also in the cerebral cortex and basal ganglia (GSS plaque) </li></ul>
  21. 21. GSS: types of point mutations <ul><li>P102L was the first to be sequenced. 32 families affected in the world. </li></ul><ul><li>A117V, formerly classified as CJD. Plaques can be diffuse, resulting from fusion of 4-10 plaques. Also kuru plaques, unicentric, without radiating spicules, 5-10 μm; amorphous plaques. </li></ul><ul><li>All plaques are PrP+ and βA4-. </li></ul>
  22. 22. Prion disease: iatrogenic CJD <ul><li>It has been associated with corneal transplantation, contaminated EEG electrode implantation, surgical operations using contaminated instruments or apparatus, dural implant and in patients receiving growth hormone (GH) treatment. </li></ul>
  23. 23. Prion disease: GH-associated CJD <ul><li>Risk is 1/200 (in individuals of same age it is 1/20 000 000). Mainly cerebellar signs; duration 6-18 months; possible incubation 4-30 years. </li></ul><ul><li>Among 16 patients 50% were V/V, 31% M/M and 19% M/V. </li></ul><ul><li>(Five cases also in women receiving human pituitary gonadotropin)+. </li></ul>
  24. 24. 四、庫魯病: <ul><li>加德賽克及迪卡斯 (Zigas) 於 1957 年描述新幾內亞東部高原的 Fore tribe 土著發生的神秘疾病。 </li></ul><ul><li>病患出現進行性的小腦退化病變,並有步履不穩、顫抖與失智現象。認為與族人吃親人遺體的習俗 (ritulistic cannibalism) 有關,尤其病患以婦女及小孩,因其主要食用死者全身各部位臟器,尤其是腦組織,而男性則以食用骨骼肌為主。自從該族改掉其吃親人遺體的習俗後,此病已近絕跡。 </li></ul>
  25. 25. Prion disease :kuru <ul><li>It begun between 1900 and 1920 as a form of sporadic CJD. Transmitted through cannibalism. Women and children most affected. </li></ul><ul><li>Transmitted after 1968 in monkeys. </li></ul><ul><li>Incubation 12-14 months. </li></ul><ul><li>Declined after cannibalism disappeared </li></ul><ul><li>Occasional new cases due to long incubation </li></ul><ul><li>Dr. WJ Hadlow (veterinary pathologist) first recognized and reported the similarity between scrapie and kuru in 1959 (The Lancet ) </li></ul>
  26. 26. Prion disease: kuru <ul><li>Macroscopic findings: atrophy of the vermis and flocculo-nodular complex </li></ul><ul><li>Histology: loss of granule and Purkinje cells, torpedoes, intense gliosis. Pattern resembling OPCA. In the cerebral cortex slight spongy degeneration. </li></ul><ul><li>Amyloid plaques in 75% of the cases, mainly in the granular layer, 15-20 μm in diameter, PAS and Conge red + </li></ul>
  27. 27. Scrapie <ul><li>First prion disease </li></ul><ul><li>Chronic CNS disease affecting sheep and goats since 1700s </li></ul><ul><li>Affecting sheep 18 months to 4.5 years of age </li></ul><ul><li>Ataxia, tremor, swaying, weakness, paralysis, excessive thirst, intense itch and loss of wool </li></ul><ul><li>Death after some months </li></ul><ul><li>In 1936 it was found, through transmission experiments, to be an infectious disease </li></ul>
  28. 28. Bovine spongiform encephalopathy (BSE) (1) <ul><li>No evidence of spread of prion from sheep to man; however, evidence of transmission of scrapie to other species through contaminated feed and pet food. </li></ul><ul><li>Transmission-related disorders include transmissible mink, feline spongiform and in zoo animals encephalopathies and BSE </li></ul>
  29. 29. BSE (2) <ul><li>BSE was identified in dairy and beef cattle in GB in 1986. Higher incidence in dairy animals as they are fed with feed. </li></ul><ul><li>Total numbers by December 2000: 180,376 in the UK, 487 in the Irish Republic, 446 in Portugal, 363 in Switzerland, 150 in France. </li></ul>
  30. 30. GSS: types of point mutations <ul><li>P102L was the first to be sequenced. 32 families affected in the world. </li></ul><ul><li>A117V, formerly classified as CJD. Plaques can be diffuse, resulting from fusion of 4-10 plaques. Also kuru plaques, unicentric, without radiating spicules, 5-10 μm; amorphous plaques. </li></ul><ul><li>All plaques are PrP+ and βA4-. </li></ul>
  31. 31. Prion disease: iatrogenic CJD <ul><li>It has been associated with corneal transplantation, contaminated EEG electrode implantation, surgical operations using contaminated instruments or apparatus, dural implant and in patients receiving growth hormone (GH) treatment. </li></ul>
  32. 32. Prion disease: GH-associated CJD <ul><li>Risk is 1/200 (in individuals of same age it is 1/20 000 000). Mainly cerebellar signs; duration 6-18 months; possible incubation 4-30 years. </li></ul><ul><li>Among 16 patients 50% were V/V, 31% M/M and 19% M/V. </li></ul><ul><li>(Five cases also in women receiving human pituitary gonadotropin)+. </li></ul>
  33. 33. 四、庫魯病: <ul><li>加德賽克及迪卡斯 (Zigas) 於 1957 年描述新幾內亞東部高原的 Fore tribe 土著發生的神秘疾病。 </li></ul><ul><li>病患出現進行性的小腦退化病變,並有步履不穩、顫抖與失智現象。認為與族人吃親人遺體的習俗 (ritulistic cannibalism) 有關,尤其病患以婦女及小孩,因其主要食用死者全身各部位臟器,尤其是腦組織,而男性則以食用骨骼肌為主。自從該族改掉其吃親人遺體的習俗後,此病已近絕跡。 </li></ul>
  34. 34. Prion disease :kuru <ul><li>It begun between 1900 and 1920 as a form of sporadic CJD. Transmitted through cannibalism. Women and children most affected. </li></ul><ul><li>Transmitted after 1968 in monkeys. </li></ul><ul><li>Incubation 12-14 months. </li></ul><ul><li>Declined after cannibalism disappeared </li></ul><ul><li>Occasional new cases due to long incubation </li></ul><ul><li>Dr. WJ Hadlow (veterinary pathologist) first recognized and reported the similarity between scrapie and kuru in 1959 (The Lancet ) </li></ul>
  35. 35. Prion disease: kuru <ul><li>Macroscopic findings: atrophy of the vermis and flocculo-nodular complex </li></ul><ul><li>Histology: loss of granule and Purkinje cells, torpedoes, intense gliosis. Pattern resembling OPCA. In the cerebral cortex slight spongy degeneration. </li></ul><ul><li>Amyloid plaques in 75% of the cases, mainly in the granular layer, 15-20 μm in diameter, PAS and Conge red + </li></ul>
  36. 36. Scrapie <ul><li>First prion disease </li></ul><ul><li>Chronic CNS disease affecting sheep and goats since 1700s </li></ul><ul><li>Affecting sheep 18 months to 4.5 years of age </li></ul><ul><li>Ataxia, tremor, swaying, weakness, paralysis, excessive thirst, intense itch and loss of wool </li></ul><ul><li>Death after some months </li></ul><ul><li>In 1936 it was found, through transmission experiments, to be an infectious disease </li></ul>
  37. 37. Bovine spongiform encephalopathy (BSE) (1) <ul><li>No evidence of spread of prion from sheep to man; however, evidence of transmission of scrapie to other species through contaminated feed and pet food. </li></ul><ul><li>Transmission-related disorders include transmissible mink, feline spongiform and in zoo animals encephalopathies and BSE </li></ul>
  38. 38. BSE (2) <ul><li>BSE was identified in dairy and beef cattle in GB in 1986. Higher incidence in dairy animals as they are fed with feed. </li></ul><ul><li>Total numbers by December 2000: 180,376 in the UK, 487 in the Irish Republic, 446 in Portugal, 363 in Switzerland, 150 in France. </li></ul>
  39. 39. BSE (4) <ul><li>Source of contamination traced to a food supplement, including meat and bone meal, related to a change in the method of processing sheep and cattle offal in the late 1970. </li></ul><ul><li>Previous techniques did inactivate the agent. </li></ul><ul><li>The British Government banned use of animal-derived feed supplements in 1988 and the epidemic has since declined. </li></ul>
  40. 40. BSE: Neuropathology <ul><li>Vacuolation occurs both in the cell body of neurones……. </li></ul><ul><li>… ..and in the grey matter and it is most severe in the brain stem </li></ul>
  41. 41. New variant CJD (nvCJD) <ul><li>First appeared in the UK in 1995; by 2002 there were some 130 verified cases. </li></ul><ul><li>The majority in the UK; 2 in France; one in the Republic of Ireland; one in Italy, one in USA, one probable case in Hong Kong. </li></ul><ul><li>Mean age 28y (15-53), mean duration 13 mo (7-38). None of the patients related to each other. </li></ul><ul><li>Epidemiological evidence relates nvCJD to BSE </li></ul>
  42. 42. nvCJD: evidence for link with BSE <ul><li>nvCJD is a new form of prion disease with unique clinical and pathological features </li></ul><ul><li>2) The majority of patients reside in the UK where BSE developed </li></ul><ul><li>3) Known incubation periods of other forms of ‘infectious’ CJD correlate with a linkage between nvCJD and BSE </li></ul><ul><li>4) Experimental work supports the link </li></ul>
  43. 43. Biochemical evidence for the BSE-vCJD link <ul><li>BSE and vCJD are caused by the same prion strain. </li></ul><ul><li>Distinct prion disease strains can be distinguished by their biological properties, including incubation periods and patterns of neuropathology on transmission to mice (known as the lesion profile). </li></ul><ul><li>PrPSc from brain tissue of different prion disease strains also shows different molecular weights and glycosylation patterns on Western blotting following partial protease digestion—characteristic profiles that are maintained on passage to mice. </li></ul><ul><li>Of the 4 PrPSc types associated with human prion diseases, type 4 is associated only with vCJD; in all vCJD cases subjected to this analysis, the type 4 pattern has been seen, and no samples from other prion diseases have shown a type 4 profile. </li></ul>
  44. 44. Biochemical evidence for the BSE-vCJD link <ul><li>Samples of BSE infected bovine brain show a profile similar to that seen in vCJD. </li></ul><ul><li>Transmission of vCJD and BSE to a mouse host and analysis of the mouse-derived PrPSc showed the same PrPSc profile, as well as similar lesion profiles distinct from those caused by other prion diseases, indicating that BSE and vCJD are indistinguishable in the same host </li></ul><ul><li>Recent cases of feline spongiform encephalopathy and related diseases in zoo animals have also shown the BSE PrPSc profile, confirming BSE as a common causative agent for the novel TSEs of the 1990s. </li></ul><ul><li>The PrPSc type is used for unequivocal diagnostic differentiation between vCJD and other prion diseases. </li></ul>

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