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British Medical Bulletin 66:121-130 (2003)
© 2003 The British Council

Neuropathology of prion diseases

Herbert Budka

Austrian Reference Centre for Human Prion Diseases (ÖRPE) and Institute of Neurology, University of Vienna, Austria

	Abstract

Top Abstract Introduction Macroscopy of human prion... Histopathology of human prion... Immunohistochemistry for the... Pathogenetic contribution Acknowledgements References

 
In prion diseases, neuropathology has remained the most important tool to give a definite diagnosis, and neuropathological research has contributed significantly to our current pathogenetic understanding. Immunohistochemistry for the disease-associated prion protein (PrP^Sc) is indispensable for the neuropathological confirmation of prion diseases. The amount and distribution of PrP^Sc deposits do not always correlate with type and severity of local tissue damage. PrP^Sc deposition occurs only where neuronal parenchyma is present; in scarred infarctions with prominent gliosis, PrP^Sc does not accumulate. Early, severe and selective loss affects a subset of inhibitory GABAergic neurons both in human and experimental prion diseases. The central pathogenetic cascade includes oxidative stress to neurons and their apoptosis. New patterns of PrP^Sc immunoreactivity include granular ganglionic and tiny adaxonal PrP^Sc deposits in peripheral nervous tissue, and dendritic cells and macrophages in vessel walls, suggesting that mobile haematogenous cells may be involved in spread of prions.

	Introduction

Top Abstract Introduction Macroscopy of human prion... Histopathology of human prion... Immunohistochemistry for the... Pathogenetic contribution Acknowledgements References

 
Neuropathology has a major role in surveillance of, and research on, prion diseases. For surveillance, it contributes diagnostic confirmation as well as potential identification of new disease (sub)types. This is important in view of the wide and steadily growing spectrum of clinical and pathological phenotypes and prion protein (PrP) gene (PRNP) genotypes. For research, it contributes to our pathogenetic understanding of prion diseases. The present brief review focuses on recently emerging points to consider in the neuropathology of human prion diseases (Table 1).

View this table: [in this window] [in a new window]   Table 1 Important points to consider and newly recognised features in the neuropathology of human prion diseases

 

	Macroscopy of human prion diseases

Top Abstract Introduction Macroscopy of human prion... Histopathology of human prion... Immunohistochemistry for the... Pathogenetic contribution Acknowledgements References

 
Gross inspection of the brain in sporadic Creutzfeldt-Jakob disease (CJD), the paramount human prion disease, may not reveal obvious abnormalities. More commonly, however, there is some degree of cerebral atrophy, which can be diffuse [Plate X(A)] or have focal accentuations. Based on preferential involvement of specific regions, occipital¹, striatal, thalamic and cerebellar² varieties have been described³. However, these subtypes are part of a spectrum of lesioning of the brain⁴. The hippocampal formation is usually well preserved even in cases of severe brain atrophy, at variance with other degenerative dementias including Alzheimer's disease. Gerstmann-Sträussler-Scheinker disease (GSS) with the classical ataxic clinical phenotype features prominent cerebellar atrophy and degeneration of spinal tracts⁵.

View larger version (101K): [in this window] [in a new window]   Plate X (A) Macroscopical aspect of a sporadic CJD brain with prominent cerebral, but not cerebellar, atrophy. (B) In sporadic CJD, some brain areas may have no (hippocampal end plate, at left), mild (subiculum, at middle) or severe (temporal cortex, at right) spongiform change. Haematoxylin and eosin (H & E) stain. (C) Cortical sections immunostained for PrPSc in sporadic CJD: synaptic (at left), patchy/perivacuolar (at middle) or plaque type (at right) patterns of PrPSc deposition. (D) Adjacent sections from sporadic CJD with pre-existing cerebellar infarctions. A preserved cerebellar cortical folium (at left) is adjacent to an infarcted one (at right) without neuronal parenchyma. The upper section is immunostained for the neuronal marker neurofilament protein, the lower section for PrPSc. PrPSc is deposited only in areas with preserved neuronal parenchyma, but not in the infarcted tissue. (E) Large Kuru-type plaque, H & E stain. (F) Typical ‘florid’ plaques in vCJD, H & E stain.

 

	Histopathology of human prion diseases

Top Abstract Introduction Macroscopy of human prion... Histopathology of human prion... Immunohistochemistry for the... Pathogenetic contribution Acknowledgements References

 
Histopathological features of human Prion diseases have been extensively described (e.g. Budka⁶) and will not be fully elaborated here. The classical triad of spongiform change, neuronal loss, and gliosis (astro- and microglia) is the neuropathological hallmark of prion diseases. Since neuronal loss and gliosis accompany many other conditions of the CNS, it is the spongiform change that is mostly specific to prion diseases. This spongiform change may be mild, moderate or severe [Plate X(B)] and is characterised by diffuse or focally clustered, small, round or oval vacuoles in the neuropil of the deep cortical layers, cerebellar cortex or subcortical grey matter, which might become confluent. Ultrastructurally, the spongiform changes correspond to enlarged cell processes (mainly neurites) containing curled membrane fragments and amorphous material⁷. Spongiform change should not be confused with non-specific spongiosis. This includes status spongiosus ('spongiform state’), comprising irregular cavities in gliotic neuropil following extensive neuronal loss (including also lesions of ‘burnt-out’ CJD), ‘spongy’ changes in brain oedema and metabolic encephalopathies, and artefacts such as superficial cortical, perineuronal, or perivascular vacuolation. Focal changes indistinguishable from spongiform change may occur in some cases of Alzheimer's and diffuse Lewy body diseases⁸. In contrast to prion diseases of animals, the presence of vacuoles in nerve cell bodies is uncommon in CJD. Ballooning of neurons observed in some instances is related to accumulation of neurofilament proteins. Spongiform changes and astocytosis may also involve the white matter^9,10. Extensive white matter degeneration distinguishes the ‘panencephalopathic’ form of CJD, which is particularly frequent in Japan¹¹.

Presence and distribution of spongiform change vary greatly between cases and disease subtypes. An almost constant location is the head of the caudate nucleus¹². By contrast, spongiform changes are rarely present in the brainstem and spinal cord, although PrP accumulation can be demonstrated at these sites. Normally, extensive sampling from various brain areas (including frontal, temporal, and occipital lobes, basal ganglia, and cerebellum) is mandatory in every suspected case. However, one block of tissue with typical histological changes and/or unambiguous PrP^Sc immunoreactivity is sufficient for a definite diagnosis. Brain biopsy has been found to be diagnostic in 95% of CJD cases in which the disease has been confirmed at autopsy or by experimental transmission¹³. However, this procedure should be restricted to rare instances where a treatable alternative diagnosis is suggested by clinical or laboratory findings.

In sporadic CJD, the regional distribution of spongiform change in distinct patterns was shown to depend upon PrP^res fragment sizes and glycotypes, and codon 129 genotype in the PrP gene, PRNP^14,15. However, some prion diseases have equivocal, little, or no spongiform change, such as fatal familial insomnia (FFI)¹⁶ that is specifically characterised by prominent thalamic atrophy with profound astrogliosis. Then immunohistochemistry for PrP and PRNP genotyping have a decisive diagnostic role¹⁷. Current neuropathological criteria for human prion diseases¹⁸, including the specific diagnostic features of variant CJD (vCJD), are listed in Table 2.

View this table: [in this window] [in a new window]   Table 2 Neuropathological criteria for CJD and other human prion diseases

 
CJD brains may also show age-related Alzheimer-type amyloid deposits immunoreactive for the ß/A4-peptide, with or without PrP^Sc co-localisation¹⁹. Neuro-axonal dystrophy may be widespread in some CJD brains²⁰.

	Immunohistochemistry for the prion protein (PrP)

Top Abstract Introduction Macroscopy of human prion... Histopathology of human prion... Immunohistochemistry for the... Pathogenetic contribution Acknowledgements References

 
Use and significance

The function of the normal cellular protein (PrP^C), the molecular prerequisite for the manifestation of any prion disease, has not been clarified. However, immunohistochemistry and other methods found it predominantly expressed in neural tissue, including neurons²¹ and glial cells²²; other organs (e.g. uterus, placenta, thymus, heart, lung, muscle, gastrointestinal tract) also contain considerable amounts²³. Up-regulation of PrP^C seems to be important in inflammatory conditions of muscle²⁴, skin²⁵ and liver²⁶, as well as in neurodegenerative disorders including Alzheimer and prion diseases²⁷.

The conformationally abnormal, disease-associated isoform (PrP^res, derived from proteinase-resistant, or PrP^Sc, the latter term derived from scrapie) accumulates in the CNS in the whole group of prion diseases and has become the most important diagnostic marker. Routine detection of PrP^Sc for diagnostic purposes uses methods such as immunohistochemistry, immunoblotting or ELISA assays performed on diseased tissue samples from patients obtained at autopsy, or from slaughtered animals as is done with current EU-wide testing of cattle for BSE and sheep for scrapie. Immunohistochemistry for PrP^Sc has emerged as an indispensable adjunct to the neuropathological confirmation of prion diseases, especially in cases with equivocal histopathological changes^8,28. It is suitable on routinely formol-fixed and paraffin-embedded tissues, although the technique may prove capricious, and pitfalls need to be considered (see below). It is noteworthy that, as for the spongiform change, PrP deposition may be focal and, in rare instances, the detection of PrP immunoreactivity may require staining of several blocks. Unfortunately, routine immunohistochemistry for PrP^Sc might yield a negative result in exceptional cases, especially in FFI¹⁶. More recently developed techniques such as the paraffin-embedded tissue blot²⁹ or the use of Carnoy's fixative³⁰ are promising alternatives to increase sensitivity for the detection of PrP^Sc in tissues. However, in our European neuropathological study of human prion diseases³¹ that now encompasses tissues from almost 1000 patients, we have seen only 2 FFI brains negative with immunohistochemistry for PrP among tissue specimens fulfilling criteria for a human prion disease.

Given the long incubation periods that make experimental transmission impractical, immunohistochemistry for PrP has also been used as a surrogate marker for infectivity in peripheral tissues that are important for considerations of infectivity risks, such as the lymphoid system³² or the peripheral nervous system^33,34. Moreover, PrP is also an important marker for development, spread and distribution of pathology. However, the amount and distribution of PrP deposits do not always correlate with type and severity of local tissue damage^16,35. In a sequential experimental study on the time course and intensity of tissue lesioning and immunohistochemistry for PrP in mice inoculated with a human CJD agent, PrP accumulation does not precede, but follows spongiform change in some brain regions³⁶. Local PrP^Sc deposition requires the local presence of neuronal, but not glial, elements: in pre-existing brain lesions such as infarctions in which neuronal elements had been focally destroyed and replaced by a gliotic scar, PrP deposition is absent [Plate X(D)]⁴.

PrP^Sc and infectivity are not uniformly distributed in an individual or animal affected with a prion disease. Two distinct groups can be distinguished: in the first, PrP^Sc and infectivity have been detected in a distribution mainly limited to the central nervous system (brain, spinal cord, parts of the eye, trigeminal and spinal ganglia). This pattern is typical of sporadic and iatrogenic CJD, genetic human prion diseases and BSE of cattle. In the second, PrP^Sc and infectivity involve also peripheral tissues, in particular the lymphoid system^37,38, and this distribution is characteristic of vCJD, natural and experimental scrapie, experimental BSE in sheep, and CWD. In all prion diseases, however, most PrP^Sc and infectivity reside in the CNS during clinical disease or late in the incubation period. This differential distribution of infectivity according to species and disease phenotype is one important factor when considering risks for transmission.

Technique and pitfalls

Since all anti-PrP antibodies that are currently used in immunohistochemistry do not distinguish between PrP^C and PrP^Sc, specific pre-treatment of tissue sections³⁹ is required for a prion disease diagnosis to abolish simultaneous reactivity with PrP^C, just as tissue extracts have to undergo proteinase K digestion before detection of PrP^res by immunoblotting. In our hands as well as those of others, a protocol using formic acid, guanidine thiocyanate, and hydrated autoclaving⁴⁰ gave the strongest and most consistent signals for formol-fixed and paraffin-embedded brain tissue. Minor modifications have been recommended⁴¹, but are not necessary for optimal immunostaining³⁹. It should be noted that the possibility of pitfalls requires extensive experience in technique and interpretation. Sometimes unspecific labelling of diffuse neuronal somata, dystrophic neurites, ß/A4 amyloid, and neurofibrillary tangles may be seen, probably representing incomplete abolishment of PrP^C immunoreactivity. Thus, diagnostic interpretation of positive labelling has to be made by experienced observers and must consider the morphology of obtained signals. Antibodies such as 6H4 and 12F10 failed to give this type of labelling and are, therefore, less likely to recognise non-pathological PrP material in immunohistochemistry³⁹.

Patterns and distribution of PrP deposition

Characteristic patterns of PrP deposition are synaptic, that is the most difficult to reveal, patchy/perivacuolar, and plaque types [Plate X(C)] and which may overlap in the individual brain⁸; sometimes prominent perineuronal deposits surround neuronal somata and processes. Frequencies of these patterns differ between cerebral and cerebellar cortex³⁵. Synaptic-type deposits and unicentric PrP plaques occur both in CJD and GSS, while abundant multicentric plaques are peculiar to GSS⁵. Plaque-like deposits are the only type of PrP deposits extending to the subcortical white matter³⁵ and are more frequent than true compact Kuru-type plaques with fringed outline that are clearly visible without immunohistochemistry [Plate X(E)]. They also stain with periodic acid-Schiff, alcian blue, Congo Red (staining disappears after formic acid treatment) and thioflavine S. Kuru plaques decorate a minority of sporadic CJD brains and are most frequent in the cerebellar cortex where they are usually confined to the granular layer. While very rarely ‘florid’ or ‘daisy-like’ plaques may be observed in other prion diseases³⁵, their prominence is restricted to vCJD [Plate X(F)]. As with spongiform change, also type and distribution of PrP deposition in sporadic CJD were shown to depend upon PrP^res fragment size and PRNP codon 129 genotype^14,15.

New patterns of PrP deposition in the PNS and vessel walls

Recently, granular ganglionic and tiny adaxonal PrP deposits were described in spinal and vegetative ganglia, spinal roots and peripheral nerves in rare cases of human prion disease³⁴ and experimental scrapie³³. It remains to be established by sequential studies whether this involvement of the peripheral nervous system reflects centripetal or centrifugal spread of PrP deposition and follows the pathways of travel by the infectious agent. In sporadic and variant CJD, we also found PrP^Sc deposits in intracranial vessel walls by immunohistochemistry and paraffin-embedded tissue blotting. Using double immunofluorescence, these deposits co-localise with HLA-DR and S-100 immunoreactive cells in the intima, which are components of the vascular-associated dendritic cell network, as well as with HLA-DR and CD-68 immunopositive macrophages of the intima and media. Thus, mobile haematogenous cells in vessel walls may be involved in the spread of disease-associated prion protein and possibly also of infectivity⁴².

	Pathogenetic contribution

Top Abstract Introduction Macroscopy of human prion... Histopathology of human prion... Immunohistochemistry for the... Pathogenetic contribution Acknowledgements References

 
One enigma of prion diseases remains the pathogenesis of brain tissue damage, in particular of neuronal drop-out and subsequent tissue loss that is usually much more striking in human than in animal and experimental prion diseases. In principle, models involving a neurotoxic gain of function (most likely for aggregated PrP^Sc)⁴³ or loss of function (of PrP^C) are conceivable and might even co-operate to manifest disease. A variety of studies were interpreted to support either model, or even both^16,44–48.

Both in human and experimental prion diseases, oxidative stress was identified as an important pathogenetic event^49,50. Neuronal loss appears to follow an apoptotic pathway that is apparently independent of local deposition of PrP^Sc but correlates with astrogliosis, microglial activation and axonal damage⁵¹. Specific vulnerability of a peculiar, parvalbumin-expressing subset of inhibitory GABAergic neurons was found both in human^52,53 and experimental prion diseases⁵⁴. In fact, this vulnerability was detectable early in the incubation period and thus represents the earliest changes ever described after experimental inoculation⁵⁴. However, FFI differs in such vulnerability⁵⁵ from all other human prion diseases. Other vulnerabilities include that of the granular layer of the cerebellum that is frequently depleted in sporadic CJD, and variable involvement of the basal nucleus of Meynert, either primarily or secondarily to cortical neuronal loss^56,57. The molecular basis for such selective neuronal vulnerabilities is still obscure.

	Acknowledgements

Top Abstract Introduction Macroscopy of human prion... Histopathology of human prion... Immunohistochemistry for the... Pathogenetic contribution Acknowledgements References

 
The Austrian Federal Ministry for Health and Women's Issues funds the Austrian Reference Centre for Human Prion Diseases (ÖRPE). The author gratefully acknowledges the collaboration of numerous European neuropathologists in the EU QoL Concerted Action PRIONET and the skilled technical assistance of Ms. Helga Flicker. Sections from vCJD brains were kindly donated by Prof. J.W. Ironside, Edinburgh).

	Footnotes

 
Correspondence to: Prof. Herbert Budka, Institute of Neurology, University of Vienna, AKH 4J, Währinger Gürtel 18–20, A-1097 Wien, Austri

	References

Top Abstract Introduction Macroscopy of human prion... Histopathology of human prion... Immunohistochemistry for the... Pathogenetic contribution Acknowledgements References

 

1. Heidenhain A. Klinische und anatomische Untersuchungen über eine eigenartige Erkrankung des Zentralnervensystems im Praesenium. Z ges Neurol Psychiatry 1929; 118: 49–114
2. Brownell B, Oppenheimer D. An ataxic form of presenile polioencephalopathy (Creutzfeldt-Jakob disease). J Neurol Neurosurg Psychiatry 1965; 28: 350–61[ISI][Medline]
3. Richardson Jr EP, Masters CL. The nosology of Creutzfeldt-Jakob disease and conditions related to the accumulation of PrPCJD in the nervous system. Brain Pathol 1995; 5: 33–41[ISI][Medline]
4. Budka H. Histopathology and immunohistochemistry of human transmissible spongiform encephalopathies (TSEs). Arch Virol (Suppl) 2000; 16: 135–42
5. Hainfellner JA, Brantner-Inthaler S, Cervenakova L et al. The original Gerstmann-Sträussler-Scheinker family of Austria: divergent clinicopathological phenotypes but constant PrP genotype. Brain Pathol 1995; 5: 201–11[ISI][Medline]
6. Budka H. Transmissible spongiform encephalopathies (prion diseases). In: Garcia JH. (ed) Neuropathology. The Diagnostic Approach. St Louis, MO: Mosby, 1997; 449–74
7. Liberski PP, Yanagihara R, Wells GA, Gibbs Jr CJ, Gajdusek DC. Comparative ultrastructural neuropathology of naturally occurring bovine spongiform encephalopathy and experimentally induced scrapie and Creutzfeldt-Jakob disease. J Comp Pathol 1992; 106: 361–81[Medline]
8. Budka H, Aguzzi A, Brown P et al. Neuropathological diagnostic criteria for Creutzfeldt-Jakob disease (CJD) and other human spongiform encephalopathies (prion diseases). Brain Pathol 1995; 5: 459–66[ISI][Medline]
9. Park TS, Kleinman GM, Richardson EP. Creutzfeldt-Jakob disease with extensive degeneration of white matter. Acta Neuropathol (Berl) 1980; 52: 239–42[Medline]
10. Macchi G, Abbamondi AL, di Trapani G, Sbriccoli A. On the white matter lesions of the Creutzfeldt-Jakob disease. Can a new subentity be recognized in man? J Neurol Sci 1984; 63: 197–206[CrossRef][Medline]
11. Mizutani T, Okumara A, Oda M, Shiraki H. Panencephalopathic type of Creutzfeldt-Jakob disease: primary involvement of the cerebral white matter. J Neurol Neurosurg Psychiatry 1981; 44: 103–15[ISI][Medline]
12. Ribadeau-Dumas JL, Escourolle R. The Creutzfeldt-Jakob syndrome: a neuropathological and electron microscopic study. In: Subirana A, Espalader JM. (eds) Neurology. Amsterdam: Elsevier, 1974; 316–29
13. Brown P, Gibbs Jr CJ, Rodgers Johnson P et al. Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 1994; 35: 513–29[CrossRef][ISI][Medline]
14. Parchi P, Giese A, Capellari S et al. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999; 46: 224–33[CrossRef][ISI][Medline]
15. Hill AF, Joiner S, Wadsworth JD et al. Molecular classification of sporadic Creutzfeldt-Jakob disease. Brain 2003; 126: 1333–46[Abstract/Free Full Text]
16. Almer G, Hainfellner JA, Brücke T et al. Fatal familial insomnia: a new Austrian family. Brain 1999; 122: 5–16[Abstract/Free Full Text]
17. Hainfellner JA, Jellinger K, Diringer H et al. Creutzfeldt-Jakob disease in Austria. J Neurol Neurosurg Psychiatry 1996; 61: 139–42[Abstract]
18. World Health Organization. Global surveillance, diagnosis and therapy of human transmissible spongiform encephalopathies: report of a WHO consultation. Geneva, Switzerland, 9–11 February 1998. Geneva: WHO, 1998; WHO/EMC/ZDI/98.9
19. Hainfellner JA, Wanschitz J, Jellinger K, Gullotta F, Budka H. Coexistence of Alzheimer type neuropathology in Creutzfeldt-Jakob disease. Acta Neuropathol 1998; 96: 116–22[CrossRef][Medline]
20. Liberski PP, Budka H. Neuroaxonal pathology in Creutzfeldt-Jakob disease. Acta Neuropathol 1999; 97: 329–34[CrossRef][Medline]
21. Kretzschmar HA, Prusiner SB, Stowring LE, DeArmond SJ. Scrapie prion proteins are synthesized in neurons. Am J Pathol 1986; 122: 1–5[Abstract]
22. Moser M, Colello RJ, Pott U, Oesch B. Developmental expression of the prion protein gene in glial cells. Neuron 1995; 14: 509–17[CrossRef][ISI][Medline]
23. Moudjou M, Frobert Y, Grassi J, Bonnardiere CL. Cellular prion protein status in sheep: tissue-specific biochemical signatures. J Gen Virol 2001; 82: 2017–24[Abstract/Free Full Text]
24. Zanusso G, Vattemi G, Ferrari S et al. Increased expression of the normal cellular isoform of prion protein in inclusion-body myositis, inflammatory myopathies and denervation atrophy. Brain Pathol 2001; 11: 182–9[ISI][Medline]
25. Pammer J, Weninger W, Tschachler E. Human keratinocytes express cellular prion-related proteins in vitro and during inflammatory skin diseases. Am J Pathol 1998; 153: 1353–8[Abstract/Free Full Text]
26. Kitada T, Seki S, Ikeda K et al. Clinicopathological characterization of prion: a novel marker of activated human hepatic stellate cells. J Hepatol 2000; 33: 751–7[Medline]
27. Voigtländer T, Klöppel S, Birner P et al. Marked increase of neuronal prion protein expression in Alzheimer's disease and human prion diseases. Acta Neuropathol (Berl) 2001; 101: 417–23[Medline]
28. Kretzschmar HA, Ironside JW, DeArmond SJ, Tateishi J. Diagnostic criteria for sporadic Creutzfeldt-Jakob-disease. Arch Neurol 1996; 53: 913–20[Abstract]
29. Schulz-Schaeffer WJ, Tschoke S, Kranefuss N et al. The paraffin-embedded tissue blot detects PrP(Sc) early in the incubation time in prion diseases. Am J Pathol 2000; 156: 51–6[Abstract/Free Full Text]
30. Giaccone G, Canciani B, Puoti G et al. Creutzfeldt-Jakob disease: Carnoy's fixative improves the immunohistochemistry of the proteinase K-resistant prion protein. Brain Pathol 2000; 10: 31–7[Medline]
31. Budka H. The human prion diseases: from neuropathology to pathobiology and molecular genetics. Final report of an EU Concerted Action. Neuropathol Appl Neurobiol 1997; 23: 416–22[Medline]
32. Hill AF, Butterworth RJ, Joiner S et al. Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 1999; 353: 183–9[CrossRef][ISI][Medline]
33. Groschup MH, Beekes M, McBride PA, Hardt M, Hainfellner JA, Budka H. Deposition of disease-associated prion protein involves the peripheral nervous system in experimental scrapie. Acta Neuropathol 1999; 98: 453–7[CrossRef][Medline]
34. Hainfellner JA, Budka H. Disease associated prion protein may deposit in the peripheral nervous system in human transmissible spongiform encephalopathies. Acta Neuropathol (Berl) 1999; 98: 458–60[CrossRef][Medline]
35. Hainfellner JA, Budka H. Immunomorphology of human prion diseases. In: Court L, Dodet B. (eds) Transmissible Spongiform Encephalopathies: Prion Diseases. Paris: Elsevier, 1996; 75–80
36. Kordek R, Hainfellner JA, Liberski PP, Budka H. Deposition of the prion protein (PrP) during the evolution of experimental Creutzfeldt-Jakob disease. Acta Neuropathol 1999; 98: 597–602[Medline]
37. Hilton DA, Ghani AC, Conyers L et al. Accumulation of prion protein in tonsil and appendix: review of tissue samples. BMJ 2002; 325: 633–4[Free Full Text]
38. Mabbott NA, Bruce ME. Follicular dendritic cells as targets for intervention in transmissible spongiform encephalopathies. Semin Immunol 2002; 14: 285–93[CrossRef][Medline]
39. Kovács GG, Head MW, Hegyi I et al. Immunohistochemistry for the prion protein: comparison of different monoclonal antibodies in human prion disease subtypes. Brain Pathol 2002; 12: 1–11[ISI][Medline]
40. Bell JE, Gentleman SM, Ironside JW et al. Prion protein immunocytochemistry – UK five centre consensus report. Neuropathol Appl Neurobiol 1997; 23: 26–35[CrossRef][ISI][Medline]
41. Van Everbroeck B, Palsa P, Martina J-J, Cras P. Antigen retrieval in prion protein immunohistochemistry. J Histochem Cytochem 1999; 47: 1465–70[Abstract/Free Full Text]
42. Koperek O, Kovacs GG, Ritchie D, Ironside JW, Budka H, Wick G. Disease-associated prion protein in vessel walls. Am J Pathol 2002; 161: 1979–84[Abstract/Free Full Text]
43. Caughey B, Lansbury Jr PT. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 2003; In press
44. Ye X, Scallet AC, Carp RI. The 139H scrapie agent produces hypothalamic neurotoxicity and pancreatic islet histopathology: electron microscopic studies. Neurotoxicology 1997; 18: 533–45[Medline]
45. Brandner S, Isenmann S, Raeber A et al. Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 1996; 379: 339–43[CrossRef][Medline]
46. Herms JW, Tings T, Dunker S, Kretzschmar HA. Prion protein affects Ca²⁺-activated K⁺ currents in cerebellar Purkinje cells. Neurobiol Dis 2001; 8: 324–30[CrossRef][ISI][Medline]
47. Kovács GG, Voigtländer T, Hainfellner JA, Budka H. Distribution of intraneuronal immunoreactivity for the prion protein in human prion diseases. Acta Neuropathol 2002; 104: 320–6[Medline]
48. Kuwahara C, Takeuchi AM, Nishimura T et al. Prions prevent neuronal cell-line death. Nature 1999; 400: 225–6[CrossRef][Medline]
49. Guentchev M, Siedlak SL, Jarius C et al. Oxidative damage to nucleic acids in human prion disease. Neurobiol Dis 2002; 9: 275–81[CrossRef][Medline]
50. Guentchev M, Voigtländer T, Haberler C, Groschup MH, Budka H. Evidence for oxidative stress in experimental prion disease. Neurobiol Dis 2000; 7: 270–73[CrossRef][Medline]
51. Dorandeu A, Wingertsmann L, Chrétien F et al. Neuronal apoptosis in fatal familial insomnia. Brain Pathol 1998; 8: 531–7[ISI][Medline]
52. Guentchev M, Hainfellner JA, Trabattoni GR, Budka H. Distribution of parvalbumin-immunoreactive neurons in brain correlates with hippocampal and temporal cortical pathology in Creutzfeldt-Jakob disease. J Neuropathol Exp Neurol 1997; 56: 1119–24[ISI][Medline]
53. Belichenko PV, Miklossy J, Belser B, Budka H, Celio MR. Early destruction of the extracellular matrix around parvalbumin-immunoreactive interneurons in Creutzfeldt-Jakob disease. Neurobiol Dis 1999; 6: 269–79[CrossRef][ISI][Medline]
54. Guentchev M, Groschup MH, Kordek R, Liberski PP, Budka H. Severe, early and selective loss of a subpopulation of GABAergic inhibitory neurons in experimental transmissible spongiform encephalopathies. Brain Pathol 1998; 8: 615–23[ISI][Medline]
55. Guentchev M, Wanschitz J, Voigtlaender T, Flicker H, Budka H. Selective neuronal vulnerability in human prion diseases. Fatal familial insomnia differs from other types of prion diseases. Am J Pathol 1999; 155: 1453–7[Abstract/Free Full Text]
56. Arendt T, Bigl V, Arendt A. Neuron loss in the nucleus basalis of Meynert in Creutzfeldt-Jakob disease. Acta Neuropathol 1984; 65: 85–8[Medline]
57. Cartier L, Verdugo R, Vergara C, Galvez S. The nucleus basalis of Meynert in 20 definite cases of Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 1989; 52: 304–9[Abstract]

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				S. Gofflot, M. Deprez, B. el Moualij, A. Osman, J.-F. Thonnart, O. Hougrand, E. Heinen, and W. Zorzi Immunoquantitative PCR for Prion Protein Detection in Sporadic Creutzfeldt-Jakob Disease Clin. Chem., September 1, 2005; 51(9): 1605 - 1611. [Abstract] [Full Text] [PDF]

				P. Rezaie, C. C. Pontikis, L. Hudson, N. J. Cairns, and P. L. Lantos Expression of Cellular Prion Protein in the Frontal and Occipital Lobe in Alzheimer's Disease, Diffuse Lewy Body Disease, and in Normal Brain: An Immunohistochemical Study J. Histochem. Cytochem., August 1, 2005; 53(8): 929 - 940. [Abstract] [Full Text] [PDF]

				R. B. Rock, G. Gekker, S. Hu, W. S. Sheng, M. Cheeran, J. R. Lokensgard, and P. K. Peterson Role of Microglia in Central Nervous System Infections Clin. Microbiol. Rev., October 1, 2004; 17(4): 942 - 964. [Abstract] [Full Text] [PDF]

				S. Cronier, H. Laude, and J.-M. Peyrin Prions can infect primary cultured neurons and astrocytes and promote neuronal cell death PNAS, August 17, 2004; 101(33): 12271 - 12276. [Abstract] [Full Text] [PDF]

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