Pathology of new variant Pathology of new variant Creutzfeldt-Jakob Creutzfeldt-Jakob

disease disease

李進成 李進成 MD PhD MD PhD

英國倫敦大學神經學研究所神經病理學博士英國倫敦大學神經學研究所神經病理學博士新光醫院病理檢驗科主治醫師新光醫院病理檢驗科主治醫師台北醫學大學及輔仁大學醫學院病理學科副教授台北醫學大學及輔仁大學醫學院病理學科副教授

Transmissible spongiform Transmissible spongiform

encephalopathies (TSE)encephalopathies (TSE) ScrapieScrapie（（綿羊搔癢症）綿羊搔癢症） 17001700ss Transmissible mink Transmissible mink

encephalopathyencephalopathy （（傳播性貂傳播性貂腦病）腦病） 19471947

Chronic wasting diseaseChronic wasting disease（（慢性消耗性病）慢性消耗性病） 19671967

Bovine spongiform Bovine spongiform encephalopathyencephalopathy （（牛海綿狀牛海綿狀腦病）腦病） 19861986

Zoo spongiform Zoo spongiform encephalopathy (encephalopathy ( 野生動物海野生動物海綿狀腦病）綿狀腦病） 19881988

Feline spongiform Feline spongiform encephalopathyencephalopathy （（貓海綿狀貓海綿狀腦病）腦病） 19901990

Creutzfeldt-Jakob Creutzfeldt-Jakob disease (CJD)disease (CJD)（（庫賈庫賈氏病）氏病） 19221922

Gerstamann-Gerstamann-Sträussler-Sträussler-Scheinker disease Scheinker disease 1936 1936

KuruKuru （（庫魯病）庫魯病） 19571957 Fatal familial Fatal familial

insomnia insomnia （（致死性家致死性家族性失眠症）族性失眠症） 19861986

Variant of CJD Variant of CJD （（變變型庫賈氏病）型庫賈氏病） 19941994

Prion (Creutzfeldt-Jakob) diseasePrion (Creutzfeldt-Jakob) disease Prion (Creutzfeldt-Jakob) disease is a unique Prion (Creutzfeldt-Jakob) disease is a unique

disorder that can occur in sporadic, acquired and disorder that can occur in sporadic, acquired and familial forms.familial forms.

It is characterized by the accumulation in the It is characterized by the accumulation in the central nervous system (CNS) of an abnormally central nervous system (CNS) of an abnormally folded isoform of a host-encoded protein, which folded isoform of a host-encoded protein, which most consider the infectious agent.most consider the infectious agent.

The pathogenesis of the sporadic form of The pathogenesis of the sporadic form of CJD is still poorly understood; instead, in the CJD is still poorly understood; instead, in the variant form (vCJD), the transmission from the variant form (vCJD), the transmission from the bovine spongiform encephalopathy has been bovine spongiform encephalopathy has been proven on biochemical, histopathological and proven on biochemical, histopathological and epidemiologic grounds.epidemiologic grounds.

Characteristic features of Characteristic features of TSETSE

A group of degenerative A group of degenerative neurological disorders causing neurological disorders causing behavioral changes, alterations behavioral changes, alterations of sensation, changes in mental of sensation, changes in mental state and ataxiastate and ataxia

Non-inflammatory vacuolation Non-inflammatory vacuolation (spongiosis) in neuronal (spongiosis) in neuronal perikarya and gray matter perikarya and gray matter neuropil, neuronal cell loss, neuropil, neuronal cell loss, gliosis, and amyloid plaquesgliosis, and amyloid plaques

Characteristic features of Characteristic features of TSE TSE

A long incubation period from A long incubation period from many months to several decadesmany months to several decades

Transmitted as an infectious Transmitted as an infectious agent by inoculation or agent by inoculation or transmitted genetically to transmitted genetically to offspring following mutation of offspring following mutation of the “prion” the “prion” (protein infectious (protein infectious organisms)organisms) protein protein （（ prion-related prion-related proteinprotein; PrP; PrP ）） gene in a parentgene in a parent

人類之人類之傳播性海綿狀腦病傳播性海綿狀腦病 庫賈氏病（庫賈氏病（ Creutzfeldt-Jakob diseaseCreutzfeldt-Jakob disease ；； CJDCJD ））

19221922 年年 : : 庫氏（庫氏（ CreutzfeldtCreutzfeldt ）報告）報告 11 例 例 22 22 歲女性歲女性患有感覺、運動及精神問題 患有感覺、運動及精神問題 (not compatible with (not compatible with current definition of CJD).current definition of CJD).

賈氏（賈氏（ JakobJakob ）報告）報告 5 5 例 “僵直性假性硬化症 例 “僵直性假性硬化症 Spastic Spastic pseudosclerosis”pseudosclerosis” ，其中有，其中有 22 例患者死亡後，經病理切例患者死亡後，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 胞消失 (non-inflammatory spongiform change and (non-inflammatory spongiform change and neuronal loss).neuronal loss).

當時認為這是一種神經退化性疾病 當時認為這是一種神經退化性疾病 (neurodegenerative disease)(neurodegenerative disease) 。 。

Kuru Kuru 庫魯病庫魯病 Gajdusek (1957) Gajdusek (1957) 年 至 新幾內亞 年 至 新幾內亞 Papau New Papau New

Guinea Guinea 東部高原的 東部高原的 Fore tribe Fore tribe 研究土著發生研究土著發生的神秘疾病。的神秘疾病。

19661966 年 年 Kuru Kuru 死亡病患之腦部切片與獸醫病理死亡病患之腦部切片與獸醫病理醫師哈德婁 醫師哈德婁 (Hadlow) (Hadlow) 討論後，得知其與綿羊搔討論後，得知其與綿羊搔癢症（癢症（ ScrapieScrapie ）的傳播性海綿狀腦病相當類似）的傳播性海綿狀腦病相當類似

於是將庫魯病病患腦部抽出物接種於非人類靈長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類動物，如黑猩猩等，而這些非人類靈長類也於12~1412~14 個月後出現與庫魯病病患類似的病症。證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 實庫魯病為一可傳播的疾病 (Transmissible (Transmissible disease)disease) 。。

CJD-TransmissibleCJD-Transmissible

加德賽克亦分別在加德賽克亦分別在 19681968 年成功的將死於庫賈氏年成功的將死於庫賈氏症症 (Sporadic CJD)(Sporadic CJD) 及在及在 19811981 年死於遺傳性庫年死於遺傳性庫賈氏症賈氏症 (Familiar CJD) (Familiar CJD) 病患腦部抽出物接種於非病患腦部抽出物接種於非人類靈長類，而這些動物也於人類靈長類，而這些動物也於 11 年後出現與庫賈年後出現與庫賈氏症病患相似的病症。氏症病患相似的病症。

當時他認為這是由於慢性病毒（當時他認為這是由於慢性病毒（ slow virus, slow virus, infectious amyloidinfectious amyloid ）或非傳統病毒）或非傳統病毒（（ unconventional virusunconventional virus ）所引起。）所引起。

傳染性蛋白粒子 傳染性蛋白粒子 prion prion (proteinaceous infectious particles) (proteinaceous infectious particles) 蒲希那（蒲希那（ PrusinerPrusiner ）於）於 19821982 年提出 年提出

prion prion 理論 ，理論 ， 認為傳播性海綿狀腦病是認為傳播性海綿狀腦病是由一種具感染性的變性蛋白質由一種具感染性的變性蛋白質 PrPsc PrPsc (scrapie prion protein) (scrapie prion protein) 引起。引起。

它會將神經細胞內正常的蛋白質 它會將神經細胞內正常的蛋白質 PrPc PrPc (cellular prion protein) (cellular prion protein) 加以轉變，而以加以轉變，而以等比級數的速度累積在神經細胞內，最後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。使腦組織形成海綿樣病變。

Sporadic CJD, clinical presentationSporadic CJD, clinical presentation

Rapidly progressive mental deterioration Rapidly progressive mental deterioration with dementia, myoclonus, motor with dementia, myoclonus, motor disturbances (pyramidal, extra-pyramidal, disturbances (pyramidal, extra-pyramidal, cerebellar, lower motor neurone) and cerebellar, lower motor neurone) and periodic short-wave activity on EEG. 15% periodic short-wave activity on EEG. 15% patients begin with ataxia (kuru-patients begin with ataxia (kuru-like).Following growth-hormone cerebellar like).Following growth-hormone cerebellar symptoms and 6-18 months duration.symptoms and 6-18 months duration.

1 case/1 000 000/year, mean age 67; 95% 1 case/1 000 000/year, mean age 67; 95% over 50y. over 50y.

Prion disease: CJD syndromesPrion disease: CJD syndromes

Showing vacuolation and no or little Showing vacuolation and no or little amyloid plaque formation.amyloid plaque formation.

Accounting for 90-95% of the total prion Accounting for 90-95% of the total prion cases, >85% are sporadic. M/F=1.2/1.cases, >85% are sporadic. M/F=1.2/1.

In sporadic cases, no family history and In sporadic cases, no family history and no ‘infectious’ episode. Infectious and no ‘infectious’ episode. Infectious and familial cases occur in younger familial cases occur in younger patients.patients.

Death in 4-12 mo, but occasionally 2-5 Death in 4-12 mo, but occasionally 2-5 years.years.

Prion disease: pathologyPrion disease: pathology

Three main features:Three main features:

1) with vacuolar degeneration and little or 1) with vacuolar degeneration and little or no amyloid plaque formation: scrapie, BSE, no amyloid plaque formation: scrapie, BSE, sporadic, iatrogenic and familial CJD, sporadic, iatrogenic and familial CJD, sporadic and familial fatal insomnia;sporadic and familial fatal insomnia;

2) abundant PrP amyloid plaque formation 2) abundant PrP amyloid plaque formation and variable vacuolar degeneration: GSS; and variable vacuolar degeneration: GSS; kuru;kuru;

3) vacuolar changes and and abundant 3) vacuolar changes and and abundant amyloid plaque formation (nvCJD). amyloid plaque formation (nvCJD).

Prion disease: neuropathology of Prion disease: neuropathology of sporadic CJDsporadic CJD

Gross appearance: Gross appearance: from no from no abnormalities to abnormalities to variable degree of variable degree of atrophy (including atrophy (including cerebellum).cerebellum).

Exceptionally very Exceptionally very low brain weight low brain weight (850 g recorded)(850 g recorded)

Prion disease: neuropathology of Prion disease: neuropathology of sporadic CJDsporadic CJD

Various subtypes: cortical; cortico-Various subtypes: cortical; cortico-striatal with/without visual loss; striatal with/without visual loss; cortico-striato-cerebellar; cortico-cortico-striato-cerebellar; cortico-spinal; cortico-nigral.spinal; cortico-nigral.

Other sub-classifications are based on Other sub-classifications are based on clinico-pathological criteria.clinico-pathological criteria.

Prion disease: sporadic CJDPrion disease: sporadic CJD

In the most severe In the most severe cases, vacuolation cases, vacuolation may become less may become less apparent due to apparent due to the loss of the loss of neurones and neurones and consequent consequent collapse of the collapse of the residual cortical residual cortical structuresstructures

Prion disease: sporadic CJD: amyloidPrion disease: sporadic CJD: amyloid

Amyloid plaques are Amyloid plaques are present in 5-10% of present in 5-10% of the cases, most the cases, most often in the often in the cerebellar granule cerebellar granule layer and resemble layer and resemble kuru plaques. They kuru plaques. They are PrP+ and are PrP+ and βA4-.βA4-.

Ultrastructurally Ultrastructurally amyloid consists of amyloid consists of fibrils.fibrils.

Prion diseases: familial formsPrion diseases: familial forms

They present at an earlier stage than They present at an earlier stage than sporadic cases.sporadic cases.

Penetrance is close to 100%, but is age-Penetrance is close to 100%, but is age-dependant: for CJD it is 1% at 40 dependant: for CJD it is 1% at 40 years, but close to 100% at 80.years, but close to 100% at 80.

This group includes:This group includes:

1) Familial CJD and1) Familial CJD and

2) Gerstmann-Str2) Gerstmann-Sträussler-Scheinker äussler-Scheinker formsforms

Gerstmann-StrGerstmann-Sträussler-Scheinker äussler-Scheinker (GSS) syndrome(GSS) syndrome

Diagnosis includes dominant Diagnosis includes dominant inheritance, cognitive and motor inheritance, cognitive and motor disturbances and widespread disturbances and widespread deposition of PrP amyloid plaques.deposition of PrP amyloid plaques.

GSS includes six disorders.GSS includes six disorders.

Its incidence is 2-5 cases/100 millionIts incidence is 2-5 cases/100 million

GSS: Clinical presentationGSS: Clinical presentation

Onset in the 4Onset in the 4thth-6-6thth decade; progression decade; progression over 6 years. over 6 years.

Difficulty in walking, unsteadiness, Difficulty in walking, unsteadiness, paresthaesia, eventually mental and paresthaesia, eventually mental and behavioural deterioration.behavioural deterioration.

OE: cerebellar ataxia, dysarthria, OE: cerebellar ataxia, dysarthria, ocular dysmetria, hyporreflexia and ocular dysmetria, hyporreflexia and extensor plantarsextensor plantars

GSS: Neuropathology GSS: Neuropathology

The hallmark of the The hallmark of the disorder is the disorder is the presence of the presence of the multicentric plaquemulticentric plaque, , most numerous in most numerous in the cerebellar the cerebellar cortex, but also in cortex, but also in the cerebral cortex the cerebral cortex and basal ganglia and basal ganglia (GSS plaque)(GSS plaque)

Prion disease: iatrogenic CJDPrion disease: iatrogenic CJD

It has been associated with corneal It has been associated with corneal transplantation, contaminated EEG transplantation, contaminated EEG electrode implantation, surgical electrode implantation, surgical operations using contaminated operations using contaminated instruments or apparatus, dural instruments or apparatus, dural implant and in patients receiving implant and in patients receiving growth hormone (GH) treatment.growth hormone (GH) treatment.

Prion disease: GH-associated CJDPrion disease: GH-associated CJD

Risk is 1/200 (in individuals of same Risk is 1/200 (in individuals of same age it is 1/20 000 000). Mainly age it is 1/20 000 000). Mainly cerebellar signs; duration 6-18 cerebellar signs; duration 6-18 months; possible incubation 4-30 months; possible incubation 4-30 years.years.

Among 16 patients 50% were V/V, 31% Among 16 patients 50% were V/V, 31% M/M and 19% M/V.M/M and 19% M/V.

(Five cases also in women receiving (Five cases also in women receiving human pituitary gonadotropin)+.human pituitary gonadotropin)+.

四、庫魯病：四、庫魯病： 加德賽克及迪卡斯 加德賽克及迪卡斯 (Zigas) (Zigas) 於於 1957 1957 年描述新年描述新

幾內亞東部高原的 幾內亞東部高原的 Fore tribe Fore tribe 土著發生的神秘土著發生的神秘疾病。疾病。

病患出現進行性的小腦退化病變，並有步履不穩、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 顫抖與失智現象。認為與族人吃親人遺體的習俗 (ritulistic cannibalism) (ritulistic cannibalism) 有關，尤其病患以婦女有關，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。該族改掉其吃親人遺體的習俗後，此病已近絕跡。

Prion disease :kuruPrion disease :kuru

It begun between 1900 and 1920 as a form of It begun between 1900 and 1920 as a form of sporadic CJD. Transmitted through cannibalism. sporadic CJD. Transmitted through cannibalism. Women and children most affected.Women and children most affected.

Transmitted after 1968 in monkeys.Transmitted after 1968 in monkeys.Incubation 12-14 months.Incubation 12-14 months.Declined after cannibalism disappearedDeclined after cannibalism disappearedOccasional new cases due to long incubationOccasional new cases due to long incubation

Dr. WJ Hadlow (veterinary pathologist) first Dr. WJ Hadlow (veterinary pathologist) first recognized and reported the similarity recognized and reported the similarity between scrapie and kuru in 1959 between scrapie and kuru in 1959 (The (The LancetLancet))

ScrapieScrapie First prion diseaseFirst prion disease Chronic CNS disease affecting sheep Chronic CNS disease affecting sheep

and goats since 1700s and goats since 1700s Affecting sheep 18 months to 4.5 Affecting sheep 18 months to 4.5

years of age years of age Ataxia, tremor, swaying, weakness, Ataxia, tremor, swaying, weakness,

paralysis, excessive thirst, intense paralysis, excessive thirst, intense itch and loss of woolitch and loss of wool

Death after some monthsDeath after some months In 1936 it was found, through In 1936 it was found, through

transmission experiments, to be an transmission experiments, to be an infectious diseaseinfectious disease

Bovine spongiform encephalopathy Bovine spongiform encephalopathy (BSE) (1)(BSE) (1)

No evidence of spread of prion from No evidence of spread of prion from sheep to man; however, evidence of sheep to man; however, evidence of transmission of scrapie to other transmission of scrapie to other species through contaminated feed species through contaminated feed and pet food.and pet food.

Transmission-related disorders include Transmission-related disorders include transmissible mink, feline spongiform transmissible mink, feline spongiform and in zoo animals encephalopathies and in zoo animals encephalopathies and BSE and BSE

BSE (2)BSE (2)

BSE was identified in dairy and beef BSE was identified in dairy and beef cattle in GB in 1986. Higher incidence cattle in GB in 1986. Higher incidence in dairy animals as they are fed with in dairy animals as they are fed with feed. feed.

Total numbers by December 2000: Total numbers by December 2000: 180,376 in the UK, 487 in the Irish 180,376 in the UK, 487 in the Irish Republic, 446 in Portugal, 363 in Republic, 446 in Portugal, 363 in Switzerland, 150 in France.Switzerland, 150 in France.

Prion disease: iatrogenic CJDPrion disease: iatrogenic CJD

It has been associated with corneal It has been associated with corneal transplantation, contaminated EEG transplantation, contaminated EEG electrode implantation, surgical electrode implantation, surgical operations using contaminated operations using contaminated instruments or apparatus, dural instruments or apparatus, dural implant and in patients receiving implant and in patients receiving growth hormone (GH) treatment.growth hormone (GH) treatment.

Prion disease: GH-associated CJDPrion disease: GH-associated CJD

Risk is 1/200 (in individuals of same Risk is 1/200 (in individuals of same age it is 1/20 000 000). Mainly age it is 1/20 000 000). Mainly cerebellar signs; duration 6-18 cerebellar signs; duration 6-18 months; possible incubation 4-30 months; possible incubation 4-30 years.years.

Among 16 patients 50% were V/V, 31% Among 16 patients 50% were V/V, 31% M/M and 19% M/V.M/M and 19% M/V.

(Five cases also in women receiving (Five cases also in women receiving human pituitary gonadotropin)+.human pituitary gonadotropin)+.

四、庫魯病：四、庫魯病： 加德賽克及迪卡斯 加德賽克及迪卡斯 (Zigas) (Zigas) 於於 1957 1957 年描述新年描述新

幾內亞東部高原的 幾內亞東部高原的 Fore tribe Fore tribe 土著發生的神秘土著發生的神秘疾病。疾病。

病患出現進行性的小腦退化病變，並有步履不穩、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 顫抖與失智現象。認為與族人吃親人遺體的習俗 (ritulistic cannibalism) (ritulistic cannibalism) 有關，尤其病患以婦女有關，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。該族改掉其吃親人遺體的習俗後，此病已近絕跡。

Prion disease :kuruPrion disease :kuru

It begun between 1900 and 1920 as a form of It begun between 1900 and 1920 as a form of sporadic CJD. Transmitted through cannibalism. sporadic CJD. Transmitted through cannibalism. Women and children most affected.Women and children most affected.

Transmitted after 1968 in monkeys.Transmitted after 1968 in monkeys.Incubation 12-14 months.Incubation 12-14 months.Declined after cannibalism disappearedDeclined after cannibalism disappearedOccasional new cases due to long incubationOccasional new cases due to long incubation

Dr. WJ Hadlow (veterinary pathologist) first Dr. WJ Hadlow (veterinary pathologist) first recognized and reported the similarity recognized and reported the similarity between scrapie and kuru in 1959 between scrapie and kuru in 1959 (The (The LancetLancet))

ScrapieScrapie First prion diseaseFirst prion disease Chronic CNS disease affecting sheep Chronic CNS disease affecting sheep

and goats since 1700s and goats since 1700s Affecting sheep 18 months to 4.5 Affecting sheep 18 months to 4.5

years of age years of age Ataxia, tremor, swaying, weakness, Ataxia, tremor, swaying, weakness,

paralysis, excessive thirst, intense paralysis, excessive thirst, intense itch and loss of woolitch and loss of wool

Death after some monthsDeath after some months In 1936 it was found, through In 1936 it was found, through

transmission experiments, to be an transmission experiments, to be an infectious diseaseinfectious disease

Bovine spongiform encephalopathy Bovine spongiform encephalopathy (BSE) (1)(BSE) (1)

No evidence of spread of prion from No evidence of spread of prion from sheep to man; however, evidence of sheep to man; however, evidence of transmission of scrapie to other transmission of scrapie to other species through contaminated feed species through contaminated feed and pet food.and pet food.

Transmission-related disorders include Transmission-related disorders include transmissible mink, feline spongiform transmissible mink, feline spongiform and in zoo animals encephalopathies and in zoo animals encephalopathies and BSE and BSE

BSE (2)BSE (2)

BSE was identified in dairy and beef BSE was identified in dairy and beef cattle in GB in 1986. Higher incidence cattle in GB in 1986. Higher incidence in dairy animals as they are fed with in dairy animals as they are fed with feed. feed.

Total numbers by December 2000: Total numbers by December 2000: 180,376 in the UK, 487 in the Irish 180,376 in the UK, 487 in the Irish Republic, 446 in Portugal, 363 in Republic, 446 in Portugal, 363 in Switzerland, 150 in France.Switzerland, 150 in France.

BSE (4)BSE (4)

Source of contamination traced to a food Source of contamination traced to a food supplement, including meat and bone supplement, including meat and bone meal, related to a change in the method of meal, related to a change in the method of processing sheep and cattle offal in the processing sheep and cattle offal in the late 1970.late 1970.

Previous techniques did inactivate the Previous techniques did inactivate the agent.agent.

The British Government banned use of The British Government banned use of animal-derived feed supplements in 1988 animal-derived feed supplements in 1988 and the epidemic has since declined.and the epidemic has since declined.

BSE: NeuropathologyBSE: Neuropathology

Vacuolation occurs Vacuolation occurs both in the cell both in the cell body of body of neurones…….neurones…….

……..and in the grey ..and in the grey matter and it is matter and it is most severe in the most severe in the brain stembrain stem

New variant CJD (nvCJD)New variant CJD (nvCJD)

First appeared in the UK in 1995; by 2002 First appeared in the UK in 1995; by 2002 there were some 130 verified cases.there were some 130 verified cases.

The majority in the UK; 2 in France; one in The majority in the UK; 2 in France; one in the Republic of Ireland; one in Italy, one in the Republic of Ireland; one in Italy, one in USA, one probable case in Hong Kong.USA, one probable case in Hong Kong.

Mean age 28y (15-53), mean duration 13 mo Mean age 28y (15-53), mean duration 13 mo (7-38). None of the patients related to (7-38). None of the patients related to each other.each other.

Epidemiological evidence relates nvCJD to Epidemiological evidence relates nvCJD to BSEBSE

nvCJD: evidence for link with BSEnvCJD: evidence for link with BSE

1)1) nvCJD is a new form of prion disease with nvCJD is a new form of prion disease with unique clinical and pathological featuresunique clinical and pathological features

2) The majority of patients reside in the UK 2) The majority of patients reside in the UK where BSE developedwhere BSE developed

3) Known incubation periods of other forms 3) Known incubation periods of other forms of ‘infectious’ CJD correlate with a of ‘infectious’ CJD correlate with a linkage between nvCJD and BSElinkage between nvCJD and BSE

4) Experimental work supports the link4) Experimental work supports the link

Biochemical evidence for the BSE-vCJD link

BSE and vCJD are caused by the same prion strain.

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).

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.

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.

Biochemical evidence for the BSE-vCJD link

Samples of BSE infected bovine brain show a profile similar to that seen in vCJD.

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

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.

The PrPSc type is used for unequivocal diagnostic differentiation between vCJD and other prion diseases.