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A range of clinical and neuropathological variants in sporadic CJD have
been described (7,32,33), the most striking of which (the panencephalic vari-
42 lronside

Fig. 3. Status spongiosis in a case of long-standing CJD shows extensive neuronal
loss in the cerebral cortex with a widespread mesh-like distribution of irregular vacu-
oles, accompanied by reactive gliosis. The cortical cytoarchitecture has collapsed
(compare with Fig. 1). Hematoxylin and eosin.

Fig. 4. Astrocytosis is widespread in CJD, with increased numbers of enlarged
astrocytes in the cerebral cortex. Astrocyte processes extend around spongiform vacu-
oles and degenerate neurons. Immunocytochemistry for glial fibrillary acidic protein.

ant) (34) contains extensive necrotizing lesions in the white matter. The histo-
logical features in these rare variants have been described largely on the basis
of traditional neuropathological staining techniques; further immunocy-
tochemical studies for PrP are required in order to more fully characterize these
unusual findings.
Around 10% of CJD cases contain PrP plaques that are usually visible as
rounded eosinophilic structures (2,3). These are most frequently observed in the
cerebellum, where they usually occur asunicentric plaques with a hyaline eosi-
Diagnosis of Human Prion Disease

Fig. 5. Increased numbers of microglia within the cerebral cortex in CJD are visu-
alized as irregular dark structures on immunocytochemistry for CD68. Microglial cell
bodies are evenly distributed throughout the cortex, with cell processes occurring
adjacent to small spongiform vacuoles.

Fig. 6. Cerebellar amyloid plaques in sporadic CJD consist of a highline core sur-
rounded by a pale halo (center). These structures are more easily observed on immu-
nocytochemistry for PrP. Hematoxylin and eosin.

nophilic core and a paler halo (Fig. 6). In kuru, these plaques often showed a
peripheral margin of radiating tibrils (26), and similar changes can be identi-
tied within plaques in sporadic (2,35) and familial CJD (20). Plaques are iden-
tified out with the cerebellum in a minority of these cases in the thalamus,
basal ganglia, or cerebral cortex. The occurrence of plaques is related to PrP
genotype and is associated with codon 129 polymorphism (being more com-
mon in met/val or val/val genotypes) (3.5); PrP plaques have also been reported
in familial CJD in association with several different PrP gene mutations (20).
44 lronsicfe

Ultrastructural and immunocytochemical studies in both human and animal
priori diseases have demonstrated that microghal cells are intimately involved
m PrP plaque formation, and may perhaps play a role m the processing of PrP
into an amyloid structure, as is thought to occur with Al3 protein in Alzheimer™s
plaques (31,36). PrP plaques share other structural similarities to Alzheimer™s
AP plaques, including the formation of neuritic processesin the plaque periph-
ery (2). Furthermore, A/3 protein has been detected mnnunocytochemically m
the periphery of some PrP plaques, although the mechanisms of this deposition
are as yet unclear (37,38).
2 2 2 Familial CJD
Molecular brological studies on human priori diseaseshave revealed an ever-
increasing number of pathogenic abnormalities in the PrP gene on chromo-
some 20 (19,20). Some of these genetic abnormalmes are associated with a
clmical phenotype mdistmguishable from sporadic CJD, whereas others exhibit
more drstmct clmical features, mcludmg predommantly cerebellar and extrapy-
ramidal signs and symptoms Many of these genetic abnormalmes are also
associated with characteristic pathological features, m particular the presence
of PrP plaques, although considerable pathological and clinical variation may
occur wtthtn affected families (20) (see Table 4).
2.2.3 latrogenic CJD
The neuropathological changes m iatrogemc CJD are variable in their char-
acter and distribution; this variability may depend on the route of moculatton
of the agent. In patients who have acquired CJD following a dura mater graft,
or implantatton of mtracerebral electrodes, the distribution of lesions m the
CNS IS very similar to those described herein for sporadic CJD, with predomi-
nantly cerebral cortical pathology (39). However, m patients who develop CJD
as a consequence of peripheral maculation with pituitary hormone prepara-
tions a different pattern of pathology is observed, which in some cases bears
more similarity to kuru than sporadic CJD (40-42). In these patients, the cer-
ebellum bears the brunt of neuropathological changes and often is markedly
atrophic with correspondingly severe neuronal loss and ghosts (Fig. 7). PrP
plaques are frequently found in this region, along with a more widespread depo-
sition of PrP within the granular layer (42) (see Chapter 4). Although
spongiform change may be observed m the cerebral cortex m such cases, it is
usually not as widespread as m sporadic CJD. Spongiform change m the basal
ganglia, however, is common and usually of marked severity. Examination of
the spinal cord m pituitary hormone-associated cases often shows plaque-like
accumulations of PrP (43), with PrP deposition m the substantia gelatmosa and
ascending pathways (see Chapter 4). However, it must be emphasized that these
Diagnosis of Human Prion Disease
Table 4
Relationship Between Pathology
and PrP Genotype in Human Prion Diseases
PrP genotype
No mutatton m open readmg frame
129 Met/Met, Met/Val
178 Asp > Asn, 129 MetNal
180 Val > Ile
200 Glu > Lys
2 10 Val > Ile
219 Glu > Lys
232 Met > Arg
Octapeptiderepeat region
48 bp msert
96 bp insert
120 bp Insert
144 bp insert
168 bp insert
192bp insert
2 16 bp insert
CJD wrth PrP plaques 129 Met/Val, VaWal
102 Pro > Leu
105 Pro > Leu
117 Ala > Val
145 Tyr Z=stop (TAG)
198 Phe > Ser
GSS with neurofibrlllary tangles
217 Gln > Arg
178 Asp > Asn, 129 Met/Met
Octapeptide repeat region
Atypical prion dementia
144 bp msert

spinal cord abnormalities are not specific for iatrogenic CJD cases and similar
patterns of PrP accumulatton have been observed in some cases of sporadic
CJD (43).
22.4. Kuru
In kuru, PrP plaque formatron was the most striking abnormality, and was
recorded as being present within the cerebellum m at least 70% of cases (26).
The typical kuru plaque is described in Section 2.2.1. and although not con-
fined to the cerebellum was most easily identified at this site. Spongtform
change was not identified m the earliest cases of kuru (44), but subsequent
46 lronside

Fig. 7. Iatrogenic CJD occurring in human growth hormone recipients shows severe
neuronal loss in the cerebellum involving the granular and Purkinje cell layers, with
widespread gliosis and severe spongifonn change in the molecular layer (compare
with Fig. 2). Hematoxylin and eosin.

investigations showed it to be present in a variable distribution in most cases
(26,45). It remains uncertain as to whether this observation was a true reflec-
tion of a change in the spectrum of pathology occurring in km-u.
2.2.5. GSS
In GSS, the characteristic abnormality is the multicentric PrP plaque, which
differs in structure from the smaller unicentric or kuru plaque (46,4 7). As their
name implies, multicentric plaques are larger, more diffuse structures that have
several core-like areas that give a positive staining reaction with Congo red,
Sirius red, and other tinctorial stains (48). These plaques are present in large
numbers in the cerebellum, within the molecular layer, granular layer, and
occasionally in the white matter. However, they are widespread also in the
cerebral hemispheres involving the cerebral cortex, basal ganglia, thalamus,
and hypothalamus. Spongiform change occurs to a variable degree in GSS; the
cerebellar molecular layer is often devoid of spongiform change, but it has
been described in the cerebral cortex, basal ganglia, and thalamus in some GSS
cases (47). There is an interesting relationship between the presence of
spongiform change and transmissibility in GSS; cases that show little or no
spongiform change (although PrP plaques are present) appear to transmit to
animals with difficulty or not at all, whereas caseswith spongiform change are
more readily transmissible (49). The cerebellum in GSS often shows severe
neuronal loss and gliosis, which is disproportionate to the neuronal loss occur-
ring in the cerebrum or spinal cord. In the Indiana variant of GSS, neurofibril-
lary tangles are present within a wide distribution in the cerebral cortex (47,X)).
Diagnosis of Human Prion Disease

This striking abnormality usually occurs in the absence of any other features
suggestive of Alzheimer™s disease.
2.2.6. Fatal Familial Insomnia
Recent studies employing molecular genetic and immunocytochemical
investigations have identified a spectrum of human prion diseases that IS
broader than hitherto suspected, resulting m the description of novel disease
entities, including fatal familial msomma (50,51) (FFI) and atypical priori
dementia (52). FFI is characterized clmically by progressive insomnia and
extrapyramidal neurological abnormalities, often m the absence of overt
dementia (.51,53).This disease is associated with a unique PrP genotype, codon
178Asn, and met/met at codon 129. The neuropathology of this entity is char-
acterized by thalamic ghosis, particularly in the dorsomedial nuclei, often in
the absence of spongiform change and m disproportionate severity to neuronal
loss. Spongiform change has been described m the cerebral cortex m occa-
sional patients with FFI, although this is not a prominent feature (53) PrP
plaque deposition has not been described m any caseto date, although cerebel-
lar atrophy and neuronal loss with ghosis m the inferior olivary nuclei have
been reported m addition to other minor and inconstant histological abnormali-
ties (51). Thalamtc gliosis m FFI is the most characteristic neuropathological
feature, although the distribution of lesions within the thalamus and associated
structures does not readily correlate with the predominant clmical features in
each case. It is also mterestmg to note that PrP deposition m this disorder is
most evident within the thalamus, both on Western blot studies and immuno-
cytochemistry (54) (see Chapter 4). Attempts to transmit disease to animals
from cases of FFI have recently been successful (55), further confirming this
entity as a priori disease.
2.2.7. Atypical Prion Diseases
The term atypical prion dementia was employed to describe dementmg 111-
nessesoccurring in young adults within a large family wtth an mhertted priori
disorder characterized by a 144-bp msert m the PrP gene (52). Initial descrip-
tions of the neuropathology m these individuals mdicated that no significant
abnormalities were present, although there was a generalrzed mild cerebral
atrophy with variable neuronal loss in the cerebrum and cerebellum. Spongi-
form change was not a prominent feature, but mrmunocytochemistry for PrP
yielded a strikmg pattern of PrP accumulation in the cerebellum (56) (see Chap-
ter 4). Other members of thts large kindred exhibited classical neuropatho-
logical features of CJD, reinforcing the phenotypic variability that may occur
in human prion diseases. Although it has been suggested that atypical priori
dementia may account for many casesof dementia that are not readily catego-
Table 5
Histological Changes in Human Prion Disease
Classical changes Spongiform change
Neuronal loss
PrP plaques
Other changes Status spongiosus
Swollen neurons
Abnormal neurltlc dendrites
Neurotic dystrophy around PrP plaques
White matter necrosis and cavitation
AP protein amylold anglopathy

rized mto precise chmcopathological entities (571, subsequent mvestigattons
on a range of other neurodegenerative disorders have failed to provide any
evidence to support this claim. Since cases of atypical priori dementia appear
to occur exclusively withm the context of inherited human priori disease, it
would seen unlikely that similar cases account for a large proportion of human

2.3. Other Histological Features in Human Prion Diseases
A range of other histologtcal abnormahties have been described m human
pi-ion diseases, some of which relate to the effect of aging on the human brain
and have no specific association with this group of disorders. These abnor-
malities include swollen cortical neurons (X$59) and amyloid angiopathy
(60,61); other changes are summarized m Table 5. It is critically important to be
aware of age-associated histological abnormalmes m the human brain and not
to interpret these as bemg indicative of a coexistmg CNS disorder (see Table 3).
Alzheimer disease and CJD been described concurrently, although this appears
to be an exceptional event (62). Other more apparently specific abnormalities
have been described m cases of CJD that have been studied by ubiquitm immu-
nocytochemistry (63). These abnormalmes include dot-like ubiquitmated struc-
tures m the neuroptl, within neurons and around PrP plaques. The latter
probably represent dystrophic neurites, whereas the mtracellular lessons may
represent lysosomal structures, as suggested by animal scrapie models (64).
2.4. Other Conditions Associated
with Spongiform-Like Change in the CNS
The importance of spongiform change as one of the histologtcal hallmarks
of human prion diseases ts widely accepted, and clear dtstmctions have been
Diagnosis of Human Prlon Disease

Table 6
Pathological Features Similar


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