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From: TSS ()
Subject: Pathology of Variant CreutzfeIdt-Jakob Disease James W. Ironside 2005
Date: August 12, 2005 at 2:07 pm PST

Pathology of Variant CreutzfeIdt-Jakob Disease

James W. Ironside

National CreutzfeIdt-Jakob Disease Surveillance Unit, Division of Pathol-
ogy, School of Molecular and Clinical Medicine, University of Edinburgh,
Western General Hospital, Edinburgh, EH4 2XU, United Kingdom

Summary. Variant CreutzfeIdt-Jakob disease (CJD) is a novel form of
human prion disease that appears to result from oral infection by the bo-
vine 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 cen-
tral nervous system, perhaps reflecting the peripheral pathogenesis of this
disorder following an oral infection with BSE. The neuropathological fea-
tures 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 pos-
sibility, 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


Transmissible spongiform encephalopathies or prion diseases are fatal neu-
rodegenerative 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 iso-
forms 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 in-
cludes 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 heterozy-
gotes [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

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


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

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 bone-
meal 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 con-
trast to sporadic CJD, the clinical and neuropathological features of variant
CJD are relatively uniform. The clinical features of variant CJD are de-
scribed in the chapter "Clinical Aspects of Variant CJD" by R. Knight in


this volume. The neuropathological features of variant CJD are summa-
rised in Table 3 and discussed in detail below.

Neuropathology of Human Prion Diseases

Human prion diseases are characterised neuropathologically by spongi-
form change, neuronal loss, glial proliferation, and (in some cases) amy-
loid plaques [3]. A histological diagnosis of prion disease can be con-
firmed 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 immunocy-
tochemistry 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 (usu-
ally 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 ill-
ness [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-

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 lay-
ers of the cortex may be involved. The occipital cortex is most severely
affected. The entorhinal cortex may show patchy microvacuolar spongi-
form 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 pri-
mary visual cortex within the occipital lobe. There is a severe loss of neu-
rones 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 brain-
stem 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 dem-
onstrated 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 vari-
ant CJD, and immunocytochemistry for tau gives negative results. PrP ac-
cumulation at the ultrastructural level has been demonstrated by immuno-
cytochemistry 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 haema-
toxylin 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].


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-


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.


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


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.



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).


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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


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.)


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
Symposium Secretariat
Kyomi Sasaki
TEL +81-22-717-8233 FAX +81-22-717-7656


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