Pathology of Variant CreutzfeIdt-Jakob Disease
James W. Ironside
National CreutzfeIdt-Jakob Disease Surveillance Unit, Division of Pathology,
School of Molecular and Clinical Medicine, University of Edinburgh, Western
General Hospital, Edinburgh, EH4 2XU, United Kingdom james.ironside@ed.ac.uk
Summary.
Variant CreutzfeIdt-Jakob disease (CJD) is a
novel form of human prion disease that appears to result from oral infection
by the bovine spongiform encephalopathy (BSE) agent. Variant CJD is also
unique in human prion diseases in that infectivity and accumulation of the
disease-associated isoform of prion protein are readily detectable outside
the central nervous system, perhaps reflecting the peripheral pathogenesis
of this disorder following an oral infection with BSE. The neuropathological
features of variant CJD are unique in terms of the histological features and
the biochemical features of the abnormal isoform of prion protein in the
brain and in lymphoid tissues. This peripheral accumulation of infectivity
has also resulted in the apparent iatrogenic transmission of variant CJD on
2 occasions, following a transfusion with non-leucodepleted red blood cells
from donors who subsequently died from variant CJD. All clinical cases of
variant CJD have so far occurred in individuals who are methionine
homozygotes at codon 129 in the prion protein gene. However, one of the
iatrogenic infections occurred in an individual who is heterozygous at this
locus, indicating the future clinical cases might also occur in this group.
Continuing surveillance of all forms of CJD is required to address this
possibility, not just in the UK but in other countries either with or at
risk of cases of BSE in the cattle population.
Key words, neuropathology, variant CJD, prion protein, immunocyto-
chemistry, biochemistry
Introduction
Transmissible spongiform encephalopathies or prion diseases are fatal
neurodegenerative disorders occurring in mammals, which include scrapie in
sheep and goats, bovine spongiform encephalopathy (BSE) in cattle, chronic
wasting disease in deer and elk and Creutzfeldt-Jakob disease (CJD) in
humans [1,2]. Prion diseases are associated with conversion of the normal
isoform of prion protein (PrPC) in the brain to an abnormal dis-
ease-associated isoform (PrPSc). PrPSc has a different conformation from
PrPC, with a higher beta-sheet content. PrPC is also relatively resistant to
proteolytic degradation; this property is used to distinguish the two
isoforms of the protein on Western blot analysis. The prion hypothesis
states that the transmissible agent in these disorders (the prion) is
composed en- tirely of PrPSc and is devoid of nucleic acid [2].
Since CJD was initially described in the 1920s, an ever- widening spec- trum
of human prion diseases has been reported (Table 1) [1]. This includes
sporadic, familial and acquired diseases, the commonest of which is the
sporadic form of CJD. The naturally occurring polymorphism at codon 129 of
the prion protein gene (PRNP) influences susceptibility to sporadic CJD
(Table 2). In comparison with normal population there is an excess of
homozygotes at codon 129 in the PRNP in sporadic CJD (particularly
methionine homozygotes), with a reduction in the percentage of heterozygotes
[3,4]. The neuropathological phenotype of sporadic CJD is variable and
appears to be influenced by the isotype of PrPSc in the brain as deter-
mined by Western blotting studies and the PRNP codon 129 genotype [4,5].
Table 1. Classification of human prion diseases
Idiopathic: Sporadic Creutzfeldt-Jakob disease
Sporadic fatal insomnia
Inherited: Gerstmann-Straussler-Scheinker syndrome and variants
Familial Creutzfeldt-Jakob disease
Fatal familial insomnia
Acquired: Human source: latrogenic Creutzfeldt-Jakob disease
Kuru
Bovine source: Variant Creutzfeldt-Jakob disease
Table 2. Codon 129 PRNP polymorphisms in CJD and normal Caucasian popula-
tion in the UK
Codon 129 Methionine/methionine methionine/valine valine/valine Polymorphism
Normal 37% 51% 12%
Sporadic CJD 66% 17% 17%
Variant CJD 100%
Surveillance of CJD in the UK was reinstated in 1990 following the
identification of a novel prion disease in cattle, known as BSE or "mad cow
disease". BSE was first reported in 1987 [6], and early epidemiologi- cal
studies indicated that it was spread by contaminated meat and bonemeal
animal feed [7]. A ban on the use of this feed allowed the disease to come
under control, but it has still not been eradicated in the UK and has
occurred in many other countries [8]. Around 180,000 clinical cases of BSE
have been identified in the UK [8], but the total number of infections
(including animals slaughtered in the preclinical stage of the illness) is
likely to have been much higher [9]. The recent widespread use of BSE
testing of slaughterhouse cattle Europe has identified cattle infected with
BSE, but had not exhibited any clinical symptoms prior to slaughter. Until
the identification of BSE, there was no evidence that other prion diseases
occurring in animals (particularly scrapie in sheep) were pathogenic to
humans. However, the observation that BSE had transmitted by the oral route
to other species (including domestic and wild cats and antelopes [8])
renewed concerns that it might represent a hazard to human health by the
consumption of BSE-contaminated meat products.
All cases of suspected CJD in the UK are referred to the National CJD
Surveillance Unit in Edinburgh by clinicians and pathologists. These cases
are investigated and subject to detailed clinical and neuropathological as-
sessment whenever possible. In 1996, the National CJD Surveillance Unit in
the UK described a novel form of human prion disease in series of 10
patients; this disease has subsequently become known as variant CJD [10].
By the end of January 2005, 154 cases of variant CJD had been identified in
the UK on the basis of clinical criteria and/or neuropathology. In contrast
to sporadic CJD, the clinical and neuropathological features of variant CJD
are relatively uniform. The clinical features of variant CJD are described
in the chapter "Clinical Aspects of Variant CJD" by R. Knight in this
volume. The neuropathological features of variant CJD are summarised in
Table 3 and discussed in detail below.
Neuropathology of Human Prion Diseases
Human prion diseases are characterised neuropathologically by spongiform
change, neuronal loss, glial proliferation, and (in some cases) amyloid
plaques [3]. A histological diagnosis of prion disease can be confirmed by
employing techniques to identify PrPSc in the brain by Western blotting,
paraffin-embedded tissue (PET) blotting, or immunocytochemis- try. Western
blot analysis on fresh or frozen brain tissues and immunocytochemistry on
paraffin sections of the brain are the commonest techniques used to identify
PrPSc [4,11,12]. Since all generally available antibodies to PrP recognise
both the PrPC and PrPSc, a limited protease digestion (usually with
Proteinase K) is required to degrade PrPc, leaving the partially digested
PrPSc to react with the antibody [4,5].
Immunocytochemistry allows the identification of different patterns of PrP
accumulation in the brain in prion diseases [11], which have enabled the
identification of different pathological subtypes of sporadic CJD [4].
In most human prion diseases there is little evidence that PrPSc is present
in tissues outside the brain, although this has been demonstrated recently
in the spleen and skeletal muscle in a subset of patients with sporadic CJD
[13]. In contrast, PrP accumulation and infectivity in lymphoid tissues is
readily detectable in other prion diseases, particularly scrapie in sheep
[14], and this feature is an important part of the pathology of variant CJD.
Neuropathology of variant CJD
The diagnostic neuropathological features of variant CJD are summarised in
Table 3.
Macroscopic features
Macroscopic examination of the brain in variant CJD shows no specific
abnormalities. Both cerebral and cerebellar cortical atrophy may occur in
cases with a prolonged clinical history (usually 2 years or longer), but
these features may be absent in cases with a short clinical duration of
illness [15]. The central white matter, basal ganglia, thalamus,
hippocampus, hypothalamus, brain stem, spinal cord and cranial nerves show
no features of note. Mild or moderate dilatation of the ventricular system
may be found as a secondary phenomenon in cases with cerebral cortical
atrophy.
Table 3. Diagnostic neuropathological features of variant CJD
1. Multiple florid plaques in H&E sections of the cerebral and cerebellar
cor- tex; numerous small cluster plaques in PrP stained sections of these
re- gions, along with amorphous pericellular and perivascular PrP accumula-
tion
2. Severe spongiform change; with perineuronal and linear periaxonal PrP ac-
cumulation in the caudate nucleus and putamen
3. Marked neuronal loss and astrocytosis in the posterior thalamic nuclei
(par- ticularly the pulvinar) and midbrain
4. Perineuronal and synaptic PrP accumulation in the grey matter of the
brain- stem and spinal cord
5. PrP accumulation around follicular dendritic cells and macrophages within
germinal centres in lymphoid tissues throughout the body
6. Predominance of di-glycosylated PrPSc on Western blot examination of
central nervous system and lymphoid tissues
Microscopic features
In the cerebral cortex, spongiform change occurs in a microvacuolar pat-
tern in a widespread, often in relation to amyloid plaques, although all
layers of the cortex may be involved. The occipital cortex is most severely
affected. The entorhinal cortex may show patchy microvacuolar spongiform
change, but this is usually absent n the hippocampus. In contrast, the
caudate nucleus and putamen are severely affected by spongiform change,
which is often confluent and not apparently related to the distribution or
number of amyloid plaques in these nuclei. Focal spongiform change is
usually present in the globus pallidus, hypothalamus and most of the tha-
lamic nuclei. The posterior thalamic nuclei (particularly the pulvinar) are
usually spared, or at the most show only mild patchy spongiform change.
Mild spongiform change is also detected in the periaqueductal grey matter in
the midbrain and in the pontine nuclei. The cerebellar cortex is variably
affected by spongiform change, which is occasionally confluent and often
associated with amyloid plaques, neuronal loss gliosis and cortical atrophy,
especially in cases with a lengthy clinical history.
In the cerebral cortex, neuronal loss is generally most severe in the
primary visual cortex within the occipital lobe. There is a severe loss of
neurones and astrocytosis throughout the cerebral cortex in cases with a
lengthy clinical history, but the hippocampal neurones are usually well
preserved. Neuronal loss in the basal ganglia is most evident in cases with
severe and confluent spongiform change. However, in the thalamus, neu- ronal
loss and astrocytosis are most severe in the posterior nuclei, particu-
larly in the pulvinar [16]. These features are not conspicuous in the
brainstem and spinal cord, but occur in the cerebellum, and usually most
severe in the vermis in cases with a lengthy clinical history, resulting in
cerebellar cortical atrophy.
The most distinctive neuropathological feature of variant CJD is the large
fibrillary amyloid plaques in the cerebral and cerebellar cortex, known as
florid plaques (Fig. 1a), which are defined as a fibrillary amyloid
structure with a dense core surrounded by a pale region of radiating
fibrils, and surrounded by spongiform change in an otherwise intact neuropil
[10].
Florid plaques can also be identified using periodic acid/Schiff and Alcian
blue stains and are strongly stained by the Gallyas silver technique [15].
Florid plaques occur in all layers of the cerebral cortex, but are most nu-
merous at the bases of the gyri. They tend to be present in largest numbers
in the occipital and cerebellar cortex (particularly in the molecular
layer).
Fibrillary amyloid plaques can also be identified in the granular layer of
the cerebellum, but without surrounding spongiform change.
Ultrastructural studies of the amyloid plaques in variant CJD have
demonstrated masses of radiating fibrils at the periphery of the plaques,
with abnormal neurites similar to those seen in Alzheimer's disease [17].
Paired helical filaments and neurofibrillary tangles are not present in
variant CJD, and immunocytochemistry for tau gives negative results. PrP
accumulation at the ultrastructural level has been demonstrated by
immunocytochemistry in plaque amyloid fibrils and some abnormal cell
membranes surrounding the plaques [18].
Immunocytochemistry for PrP
The florid plaques in the cerebral cortex and cerebellum give an intense
positive reaction on immunocytochemistry for PrP (Fig. 1b) [15]. Smaller
"cluster plaques" (which cannot be identified in sections stained by
haematoxylin and eosin) are also revealed by immunocytochemistry for PrP in
these regions, along with a widespread amorphous pericellular deposition of
PrP around glial cells and small neurones.
Fig. 1a-d. a. A florid plaque in the occipital cortex in a 20 year old male
with a 20-month clinical history of variant CJD. The plaque has a dense
eosinophilic core with a pale fibrillary periphery and is surrounded by a
rim of spongiform change. Scale bar is 25 um. b. Immunocytochemistry for PrP
in the occipital lobe in variant CJD (same case as Fig. 1a) shows intense
labelling of the florid plaques, but also (KG9 anti-PrP antibody). Scale bar
is 50 um. c. Accumulation of PrP is revealed by immunocytochemistry in
sensory ganglion cells within the dorsal root ganglia in variant CJD (6H4
anti-PrP antibody). Scale bar is 25 um. d. Immuno- cytochemistry for PrP
shows labelling of follicular dendritic cells within a germi- nal centre
within the tonsil from an autopsy case of variant CJD. This finding is also
present in tonsil biopsies on patients with variant CJD (12F10 anti-PrP
anti- body). Scale bar is 50 um.
In the basal ganglia, there is a predominantly perineuronal pattern of PrP
immunoreactivity which is often linear and apparently periaxonal. A syn-
aptic pattern of PrP accumulation with occasional plaques is detected in the
thalamus, but the linear pattern of PrP accumulation is usually absent.
There is a dense synaptic accumulation in the dentate fascia, in the hippo-
campus and also in the subiculum and entorhinal cortex. PrP positivity in a
synaptic pattern is present in the brainstem and spinal cord in the grey
matter, particularly in the substantia gelatinosa. The leptomeninges (in-
cluding the arachnoid granulations) and dura mater give a negative reac-
tion for PrP on immunocytochemistry.
The severe astrocytosis in the posterior thalamic nuclei is best demon-
strated on immunocytochemistry for glial fibrillary acidic protein [16].
This technique also demonstrated astrocytosis in other areas of severe neu-
ronal loss, and less frequently around the margins of florid plaques.
Quantitative pathology
Quantitative histological studies on the first cases of variant CJD con-
firmed that the measurable accumulation of PrP deposits in the cerebellum
was far greater than in sporadic CJD cases [19]. The severe gliosis in the
pulvinar within the posterior thalamus was also confirmed, with measured
levels of astrocytosis far in excess of sporadic CJD cases [19]. Subsequent
quantitative studies have shown that the relationship between the spongi-
form change and the presence of amyloid plaques varies in different brain
regions in variant CJD [20,21]. Analysis of the spatial patterns of abnor-
mal PrP deposition in variant CJD has found no significant differences be-
tween different regions of the cerebral cortex [22]. Textural analysis tech-
niques to investigate the differences in patterns of abnormal PrP deposition
in the brain in variant CJD are currently under development [23].
Non-CNS tissues
PrP accumulation is identified in the retina and optic nerve, spinal dorsal
root ganglia (Fig. Ic) and trigeminal ganglia in variant CJD. However, pe-
ripheral sensory and motor nerves contain no detectable PrP [24,25]. The
pineal gland and the posterior pituitary gland usually show synaptic posi-
tivity for PrP, but the anterior pituitary gland shows no PrP accumulation.
PrP immunocytochemistry in other main organs (including the adrenal gland,
thyroid gland, parathyroid gland, skeletal muscle, bladder, testes, female
pelvic organs, heart, lung, liver, kidney, oesophagus, stomach, pan- creas,
gall bladder, salivary gland and skin) is negative [5,15,24].
In contrast, PrP accumulation is identified around follicular dendritic
cells and macrophages within many germinal centres in the tonsils (Fig.
1d) and in gut-associated lymphoid tissues in the appendix and Peyer's
patches in the ileum, spleen, lymph nodes from the cervical, mediastinal,
para-aortic and mesenteric regions and the thymus [5,15,26]. Quantitative
studies of PrP accumulation in lymphoid tissues in variant CJD indicate that
lymph nodes and the tonsil are most likely to contain a high percent-
age of PrP-positive germinal centres than the spleen or gut-associated
lymphoid tissues [24].
Biochemistry
Biochemical studies of PrPSc by Western blot analysis can be used to sub-
classify cases of CJD by comparing the relative abundance of the non-
glycosylated, mono-glycosylated and di-glycosylated forms of the protein and
measuring the mobility of the non-glycosylated form [4,15]. In spo- radic
CJD, two major PrPSc isoforms have been described, termed type 1 and type 2
[4] (Fig. 2). The non-glycosylated fragment of type 1 has a mo- lecular
weight of 21kDa and the non-glycosylated fragment of type 2 has a molecular
weight of 19kDa. In variant CJD, the mobility of the non- glycosylated
portion of PrPres is similar to that of type 2 [15,24]. In spo- radic CJD
type 2, the mono-glycosylated form predominates and is re- ferred to as type
2A [4,15]. However, the di-glycosylated form of PrPSc predominates in
variant CJD, so the isoform is termed type 2B (Fig. 2). A similar PrPSc
glycosylation pattern to that type 2B PrPSc isoform in variant CJD has been
identified in BSE and in other BSE-related conditions in other species [27].
Type 1 2A 2B 1 2A 2B
PK - - - + + +
Fig. 2. Western blot analysis of prion protein in samples of cerebral cortex
from two cases of sporadic CJD (type 1, type 2A) and a case of variant CJD
(type 2B).
The samples are shown before (-) and after (+) digestion with proteinase
K(PK).
The protease-resistant prion protein is classified as type 1 (21kDa non-
10
glycosylated lower band) or type 2 (19kDa non-glycosylated lower band). The
type found in variant CJD is characterised by the predominance of the upper
(*) diglycosylated band, and termed type 2B to distinguish it from that
found in spo- radic which is characterised by the predominance of the middle
monoglycosylated band and termed type 2A.
Discussion
Variant CJD is the only human prion disease which appears to result from an
acquired infection from a non-human species [27-29], namely from BSE in
cattle. Experimental transmission studies have confirmed that the
transmissible agent in variant CJD is very similar to the BSE agent, but
different from the agent in sporadic CJD [27-29]. It is likely that most
human exposure to BSE occurred by the consumption of contaminated beef
products. Variant CJD is also distinct from other human prion dis- eases in
terms of the widespread distribution of the infectious agent in the body,
possible reflecting an oral exposure to the BSE agent responsible for
this disorder. PrPSc has been identified by immunocytochemistry and Western
blot examination in lymphoid tissues in variant CJD, and experi- mental
transmission studies have confirmed that infectivity is present in these
tissues, although at levels which are lower than in the brain [30].
This finding has caused concerns that variant CJD may be transmitted ac-
cidentally, by surgical instruments used on lymphoid tissues (such as in
tonsillectomy procedures), or by blood transfusion or blood products [31].
The concerns over potential infectivity in blood in variant CJD were re-
cently reinforced by the experimental transmission of BSE by blood trans-
fusion in a sheep model, at a preclinical stage in the infection [14]. A
case of variant CJD has been identified in the UK in an individual who
received a single unit of non-leucodepleted red blood cells from a donor who
had died from variant CJD 7.5 years previously, representing the first
possible case of "iatrogenic" variant CJD [32]. The clinical,
neuropathological and biochemical features of this case were entirely
typical of variant CJD and the patient was a methionine homozygote at codon
129 in the PRNP gene.
Recently, a second case of apparent iatrogenic transmission of variant CJD
was reported in an elderly female who died with no history of neurological
disease 5 years after receiving a single unit of non-leucodepleted red blood
cells from a donor who subsequently died from variant CJD [33]. The re-
cipient was a heterozygote at codon 129 in the PRNP gene, and showed no
pathological or biochemical evidence of variant CJD in the central nervous
system. However, PrPSc was identified by immunocytochemistry in the spleen
and a cervical lymph node and Western blot analysis of the spleen
11
showed a biochemical profile similar to that in variant CJD [33]. Interest-
ingly, PrP accumulation was not present in the tonsil or appendix, perhaps
reflecting an intravenous (rather than oral) route of infection. This case
also indicates that PRNP codon 129 heterozygotes are susceptible to infec-
tion with variant CJD, but may have a different incubation period before the
onset of clinical disease.
The diagnostic pathological features of variant CJD are summarised in Table
3. It is noteworthy that the presence of florid plaques alone is not
diagnostic of variant CJD, since florid PrP amyloid plaques have been de-
scribed in cases of iatrogenic CJD following dura mater graft procedures
[34], although the number and distribution of these lesions in the brain is
more restricted than in variant CJD. The biochemical features of PrPSc in
the brain in variant CJD on Western blot examination is relatively uniform
[5], in contrast to sporadic CJD, where multiple PrPSc isoforms have been
identified, and can co-exist even within a single case [35]. However, a
similar brain PrPSc isotype to that found in variant CJD has been reported
in a recent atypical case of sporadic CJD [36], reinforcing the need for the
detailed study of human prion diseases by a combination of clinical, patho-
logical, genetic and biochemical studies. As BSE continues to spread across
the world, it can be anticipated that future cases of variant CJD will be
identified in other countries.
Prediction of the future numbers of variant CJD cases in the UK and
elsewhere remains difficult because of the uncertainties concerning the
number of individuals incubating the disease and the likely incubation pe-
riod, which may be influenced by genetic factors including the codon 120
polymorphism in the PRNP gene. Although there was earlier evidence of an
increase in the incidence of the disease in the UK, this has not been sus-
tained and the rate of increase in the number of cases is now declining
[37]. A recent retrospective immunocytochemical study of PrP accumula- tion
in a series of over 12,00 appendicetomy and tonsillectomy specimens in the
UK found three positive cases, indicating that the prevalence of BSE
infection in the UK population may be higher than the numbers of clinical
cases of variant CJD would so far indicate [38]. This unexpected finding
might possibly result from different incubation periods in different genetic
subgroups at codon 129 in the PRNP gene and could indicate that further
rises in the numbers of variant CJD cases may occur in the future. Contin-
ued surveillance for all forms of CJD is required to answer these questions,
and neuropathology is a key part in the investigation and characterisation
of such cases.
12
Acknowledgements
This study would not have been possible without the generous co- operation
of all the neuropathologists in the United Kingdom. I thank Dr Mark Head for
providing Figure 2, Ms S Lowrie and Mrs M LeGrice for expert technical
assistance, and Ms D Ritchie for photographic assistance.
The National CJD Surveillance Unit is funded by the Department of Health and
the Scottish Executive Department of Health; the Unit is a member of the
TSELAB project funded by the EC (QLK2-CT-2002- 81523). This work is part of
the EU NeuroPrion project (FOOD-CT-2004-
506579 (NOE) subproject: PRIOGEN).
References
1. Ironside JW (1998) Prion diseases in man. J Pathol 186:227-234
2. Prusiner SB (1998) Prions. Proc Nati Acad Sci USA 95:13363-13383
3. Ironside JW (1996) Creutzfeldt-Jakob disease. Brain Pathol 6:379-388
4. Parchi P, Giese A, Capellari S, et al (1999) Classification of sporadic
Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300
subjects. Ann Neurol 46:224-233
5. Ironside JW, Head MW, Bell JE, et al (2000) Laboratory diagnosis of
variant Creutzfeldt-Jakob disease. Histopathology 37:1-9
6. Wells GA, Scott AC, Johnson CT, et al (1987) A novel progressive spongi-
form encephalopathy in cattle. Vet Rec 121:419-420
7. Wilesmith JW, Wells GA, Cranwell MP, et al (1988) Bovine spongiform en-
cephalopathy: epidemiological studies. Vet Rec 123: 638-644
8. Department of the Environment, Food and Rural Affairs (2004) Bovine
spongiform encephalopathy in Great Britain. A progress report. DEFRA Pub-
lications, London
9. Anderson RM, Donnelly CA, Ferguson NM, et al (1996) Transmission dy-
namics and epidemiology of BSE in British cattle. Nature 382:779-788
10. Will RG, Ironside JW, Zeidler M, et al (1986) A new variant of
Creutzfeldt- Jakob disease in the UK. Lancet 347: 921-925
11. Bell JE, Gentleman SM, Ironside JW, et al (1997) Prion protein
immunocyto- chemistry - UK five-centre consensus report. Neuropathol Appi
Neurobiol
23:26-35
12. Ritchie DL, Head MW, Ironside JW (2004) Advances in the detection of
prion protein in peripheral tissues of variant Creutzfeldt-Jakob disease pa-
tients using paraffin-embedded tissue (PET) blotting. Neuropathol Appi
Neurobiol 30:360-368
13. Glatzel M, Abela E, Maissen M, et al (2003) Extraneural prion protein in
sporadic Creutzfeldt-Jakob disease. New Eng J Med 349:1812-1820
14. Hunter N, Foster J, Chong A, et al (2002) Transmission of prion diseases
by blood transfusion. J Gen Virol 83:2897-2905
15. Ironside JW, McCardle L, Horsburgh A, et al (2002) Pathological
diagnosis of variant Creutzfeldt-Jakob disease. APMIS 11:79-87
16. Zeidler M, Sellar RJ, Collie DA, et al (2000) The pulvinar sign on
magnetic resonance imaging in variant Creutzfeldt-Jakob disease. Lancet
355:1412-
1418
17. Liberski PP, Ironside J, McCardle L, et al (2000) Ultrastructural
analysis of the florid plaque in variant Creutzfeldt-Jakob disease. Folia
Neuropathol 38:167-170
18. Fournier JG, Kopp N, Streichenberger N, et al (2000) Electron microscopy
of brain amyloid plaques from a patient with new variant Creutzfeldt-Jakob
dis- ease. Acta Neuropathol 99:637-642
19. Ironside JW, Sutherland K, Bell JE, et al (1996) A new variant of
Creutzfeldt- Jakob disease: neuropathological and clinical features. Cold
Spring Harb Symp Quant Biol 61:523-530
20. Armstrong RA, Cairns NJ, Ironside JW, et al (2002) Quantification of
vacuo- lation ("spongiform change"), surviving neurones and prion protein
deposi- tion in eleven cases of variant Creutzfeldt-Jakob disease.
Neuropathol Appi Neurobiol 28:129-135
21. Armstrong RA, Cairns NJ, Ironside JW, et al (2002) Quantitative
variations in the pathology of 11 cases of variant Creutzfeldt-Jakob disease
(vCJD). Patho- physiology 8:35-241
22. Armstrong RA, Cairns NJ, Ironside JW, et al (2002) The spatial patterns
of prion protein deposits in cases of variant Creutzfeldt-Jakob disease.
Acta Neuropathol 104:665-669
23. Head MW, Northcott V, Rennison K, et al (2003) Prion protein
accumulation in eyes of patients with sporadic and variant Creutzfeldt-Jakob
disease. Invest Ophthalmol Vis Sci 44:342-346
24. Nailon WH, Ironside JW (2000) Variant Creutzfeldt-Jakob disease: immuno-
cytochemical studies and image analysis. Microsc Res Tech 50: 2-9
25. Head MW, Ritchie D, Smith N, et al (2004) Peripheral tissue involvement
in sporadic, iatrogenic and variant Creutzfeldt-Jakob disease: an
immunohisto- chemical, quantitative and biochemical study. Am J Pathol
164:143-153
26. Hill AF, Butterworth RJ, Joiner S, et al (1999) Investigation of variant
Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy
samples. Lancet 353:183-189
27. Collinge J, Sidle KCL, Meads J, et al (1996) Molecular analysis of prion
strain variation and the aetiology of "new variant" CJD. Nature 383:685-690
28. Bruce ME, Will RG, Ironside JW, et al (1997) Transmissions to mice
indicate that "new variant" CJD is caused by the BSE agent. Nature
389:498-501
29. Scott MR, Will R, Ironside J, et al (1999) Compelling transgenetic
evidence for transmission of bovine spongiform encephalopathy prions to
humans.
Proc Nati Acad Sci USA 96:15137-15142
14
30. Bruce ME, McConnell I, Will RG, et al (2001) Detection of variant
Creutzfeldt-Jakob disease infectivity in extianeural tissues. Lancet
358:208-
209
31. Turner ML, Ironside JW (1998) New-variant Creutzfeldt-Jakob disease: the
risk of transmission by blood transfusion. Blood Rev 12:255-268
32. Llewelyn CA, Hewitt PE, Knight RSG, et al (2004) Possible transmission
of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet
363:417-421
33. Peden AH, Head MW, Ritchie DL, et al (2004) Preclinical vCJD after blood
transfusion in a PRNP codon 129 heterozygous patient. Lancet 364:527-529
34. Shimizu S, Hoshi K, Muramoto T, et al (1999) Creutzfeldt-Jakob disease
with florid-type plaques after cadaveric dura mater grafting. Arch Neurol
56,:357-
363
35. Puoti G, Giaccone G, Rossi G, et al (1999) Sporadic Creutzfeldt-Jakob
dis-
ease: co-occurrence of different types of PrP(Sc) in the same brain. Neurol-
ogy 53:2173-2176
36. Head MW, Tissingh G, Uitdehaag BM, et al (2001) Sporadic Creutzfeldt-
Jakob disease in a young Dutch valine homozygote: atypical molecular phe-
notype. Ann Neurol 50:258-261
37. Andrews NJ, Farrington CP, Ward HJ, et al (2003) Deaths from variant
Creutzfeldt-Jakob disease in the UK. Lancet 361:751-752
38. Hilton DA, Ghani A, Conyers L, et al (2004) Prevalence of
lymphoreticular prion protein accumulation in UK tissue samples. J Pathol
203:733-39
END
International Symposium of Prion Diseases held in Sendai, October 31, to
November 2, 2004.
The hardback book title is 'PRIONS' Food and Drug Safety T. Kitamoto (Ed.)
SPRINGER
Tetsuyuki Kitamoto
Professor and Chairman
Department of Prion Research
Tohoku University School of Medicine
2-1 SeiryoAoba-ku, Sendai 980-8575, JAPAN TEL +81-22-717-8147 FAX
+81-22-717-8148 e-mail; kitamoto@mail.tains.tohoku.ac.jp Symposium
Secretariat Kyomi Sasaki TEL +81-22-717-8233 FAX +81-22-717-7656
e-mail: kvomi-sasaki@mail.tains.tohoku.ac.ip