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to Spongiform Change Seen in Other Neurodegenerative Diseases
Alzhelmer™s disease
CNS disorders with focal sponglform change
Pick™s disease
Diffuse Lewy body disease
Dementia m motor neuron disease
Dementia of frontal lobe type
Sponge-like changes in other CNS disorders
Status spongiosis
Gay matter
Edema
Metabolic encephalopathles
Neuronal storage disorders
Tissue fixation and processmg
Artifacts
White matter Edema
Ischemla
Metabohc encephalopathles
Canavan disease
Spongy degeneration of the white
matter m infancy
Tissue fixation and processmg
artifacts


made between sponglform change and status sponglosls. Status sponglosis can
result from any neurodegenerative disorder that results in widespread neuronal
death and collapse of the cerebral cortical cytoarchltecture. It ts encountered
commonly m Pick™s disease and may also occur m Alzhelmer™s disease, cortl-
cal ischemla, and as a consequence of viral encephalitis. Sponglform change
per se 1snot pathonomonic for human prlon diseases.Appearances identical to
sponglform change have been described in other neurodegeneratlve disorders
(see Table 6), particularly m Alzhelmer™s disease and diffuse Lewy body dls-
ease (65) (Fig. 8). In these disorders spongiform change 1susually confined to
layer 2 of the cerebral cortex and 1spresent in a restricted distribution m the
frontal lobes, cmgulate gyrus, temporal poles, and mferlor temporal cortex.
The basal ganglia, thalamus, hypothalamus, cerebellum, and spinal cord m
these disorders do not show spongiform change. In occasional cases of
Alzhelmer™s disease and diffuse Lewy body disease the sponglform change
may be particularly conspicuous and necessitate widespread histological sam-
pling along with additlonal investigative techniques, including PrP immunocy-
tochemlstry, to investigate the possibility of human prlon disease. It should
also be recalled that other neurodegeneratlve disorders resultmg m focal
50 lronside




Fig. 8. Spongiform change in diffuse Lewy body disease tends to occur in a charac-
teristic distribution in the inferior frontal and temporal lobes. Numerous small vacu-
oles are present throughout the cortex, but there is usually less evidence of confluent
vacuolation in this condition than in sporadic CJD (compare with Fig. 1). Hematoxy-
lin and eosin.


spongiform-like change are associated with distinctive lesions that help clarify
diagnosis. Other disorders that may cause a sponge-like appearance in the CNS
are listed in Table 6. In these disorders, confusion with spongiform change in
human prion disease is not a major difficulty because of the clinical and patho-
logical context in which these changes occur (Figs. 9 and 10).

3. Relation of Neuropathology to Host Genotype
As mentioned earlier, the molecular biological studies on human prion dis-
orders have revealed a wide range of abnormalities in the PrP gene in familial
prion disorders. The importance of the influence of PrP genotype on both clini-
cal and pathological features is well illustrated by the effect of the codon 129
genotype in patients with a codon 178Asn mutation, since this influences pre-
sentation either as familial CJD (met/val genotype) or FFI (met/met genotype)
(54). Even in the absence of PrP gene mutations, codon 129 genotype appears
to confer disease susceptibility for both sporadic and iatrogenic CJD (66,67);
codon 129 genotype also influences PrP plaque formation in sporadic CJD,
which occurs most frequently in patients with a met/val or val/val genotype
(67). Other genes may also influence clinical and pathological features in
human prion diseases, including the apolipoprotein E gene on chromosome 19
(35). As in Alzheimer disease, the ApoE e4 genotype is more common in cases
of sporadic CJD than in age-matched normal control cases, and in affected
individuals the ApoE e2 allele appears to be associated with a more prolonged
clinical course, independent of any PrP gene abnormalities (68). Whether these
Diagnosis of Human Prion Disease 51




Fig. 9. Cerebral edema can occasionally result in multiple irregular vacuoles within
the neuropil of the cerebral cortex, accompanied by a marked retraction artifact around
blood vessels and individual cell bodies. This usually can be distinguished easily from
spongiform change (compare with Fig. 1). Hematoxylin and eosin.




Fig. 10. Cerebellar edema occurring with hypoxic brain damage occasionally results
in the appearance of multiple small vacuoles in the molecular layer, particularly in its
superficial aspect (compare with Figs. 2 and 7). Hematoxylin and eosin.


findings are relevant to disease susceptibility is uncertain, and the influence of
ApoE genotype on neuropathology has not yet been fully evaluated.

4. Recent Developments in Neuropathology
Neuropathological studies in human prion diseaseshave been greatly facili-
tated by the development of reliable techniques for PrP immunocytochemistry
(69) (see Chapter 4). This technique has revealed an entirely unsuspected spec-
trum of pathology, although the relationship between PrP deposition and other
52 lronside
classical neuropathological features 1sas yet unclear. In order to address this
question, and to help provide a more precise analysis of neuropathological
changes m CJD, computer-based image analysis techmques have been devel-
oped to evaluate the neuropathology of human priori diseases m a subJective
manner (70). To date, successful programs have been developed to quantita-
tively assessspongiform change, PrP deposition as revealed by nnmunocyto-
chemistry, and astrocytosis Prelimmary application of these validated
techniques to human priori diseaseshas demonstrated a variation m the relative
mvolvement of the cerebral cortex and basal ganglia m terms of PrP deposi-
tion, spongiform change, and astrocytosis m relation to PrP genotype One
major advantage of this automated quantitative approach IS the ability to ana-
lyze numerous large sections of the human bram, allowmg a representative
survey of neuropathology without observer bias or fatigue
Other recent neuropathological investigations m human prion diseases have
mcluded the use of confocal scanning laser microscopy (71) to mvestlgate the
complex structural changes occurrmg m relation to spongiform change and
PrP plaque formation. The use of confocal laser microscopy with mununocy-
tochemistry, and the ability to serially reconstruct three-dimensional images
from thick (60˜pm) brain sections will allow a more detailed understanding of
cellular mteracttons m the development of classtcal neuropathologlcal abnor-
mallties. Electron microscopy m human priori diseaseshas not been employed
as an mvestigative tool to a large extent (particularly in comparison with stud-
ies on the neuropathology of animal scrapte models) partly because of difficul-
ties encountered with postmortem autolysis and the relative unavailability of
rapidly fixed cortical biopsy specimens. However, immunocytochemrcal tech-
niques for PrP m the murine scrapte model have been developed at the ultra-
structural level (64) (see Chapter 4), which should be applied to the tine structural
changes occurrmg m human priori disease m relation to PrP deposition Ultra-
structural mvesttgations of animal and human priori diseases have reported the
presence of tubulovesicular bodies (72,73), which are apparently specttic for this
group of disorders, although then- precise nature and significance m relation to
the transmissible agents responsible for these diseases remams uncertain.
5. Conclusion
The enormous Increase in knowledge of the protein chemistry, biochemis-
try, and molecular biology of priori diseasesm humans has been accompanied
by a renewed interest m the neuropathology of this fascinating group of drs-
eases.The broadening spectrum of human priori diseasesencompassesa wider
range of clinicopathologlcal entitles than suspected a decade ago, whereas the
refinement of immunocytochemlcal techniques for PrP and other proteins m
the bran-r has allowed a more detailed study of cellular reactions and structural
Diagnosis of Human Pnon Disease 53
abnormalities m the CNS The development of quantltatlve techmques to ana-
lyze these neuropathologlcal abnormalities will facilitate a further understand-
mg of the relatlonshlp between genotype, clintcal features, and neuropathology
in sporadic, latrogenic, and familial forms of human prlon disease. The recog-
nition that many of the neuropathological abnormahtles m human prlon dls-
eases are not exclusive to this group of disorders, but may occur m other
diseases (21,741, has reinforced the concept of common mechanisms operatmg
m a range of neurodegenerative disorders and has also prompted efforts to
develop more specific neuropathological diagnostic Investigations.

Acknowledgments
I am grateful to J. E. Bell, R. Will, R. de Silva, I. Goodbrand, and K. Sutherland for
helptil discussion; to L. McCardle, C. Bame, and D. Nlcolson for technical assis-
tance; and S. Honeyman for preparmg the manuscript. The Nattonal CJD Surveillance
Unit 1ssupported by the Department of Health, BBSRC (AG 15/610) and MRC.
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