Prion diseases

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Prion diseases

The designation of prion diseases as a distinct nosologic category is based on the elucidation of a novel molecular pathology that is common to several disorders previously known as spongiform encephalopathies, unconventional viral infections, or transmissible dementias. These include the following human diseases:

Common to all of these diseases are:

image CELL BIOLOGY OF PRION DISEASE

The prion diseases have a common molecular pathology that involves the conversion of a normal cellular protein called prion protein (PrP) into an abnormal isoform (Fig. 32.1). Most evidence implicates the abnormal protein as the transmissible factor; evidence is lacking for the involvement of DNA or RNA in the infective process.

Definitions

Prion

Agent of transmissible spongiform encephalopathy (TSE) with unconventional properties. The term does not have structural implications other than that a protein is an essential component

PrPC or PrP sen

The naturally occurring form of the mature PRNP gene product. Its presence in a given cell type is necessary, but not sufficient, for replication of the prion. The terms PrPC (cellular PrP) and PrPsen (proteinase-sensitive) are both used (Fig. 32.2).

PrPSc (other terms PrP res or PrPCJD)

‘Abnormal’ form of the mature Prnp gene product (Fig. 32.3). Partly resistant to digestion by proteinase K. Believed to differ from PrPC conformationally. Often considered to be the transmissible agent or prion. The designations PrPSc (from scrapie, the spongiform encephalopathy of sheep); PrPCJD (CJD-associated PrP); PrPres (protease resistant); PrP*, and PrPP have all been used for this form of PrP.

‘Protein-only’ hypothesis

This maintains that the prion is devoid of informational nucleic acid, and that the essential pathogenic component is protein (or glycoprotein). Genetic evidence indicates that the protein is an abnormal form of PrP. The association with other non-informational molecules (such as lipids or glycosaminoglycans) is not excluded.

PrP in normal function and disease

PrPC (‘cellular’ PrP)

In prion disease PrPSc (abnormal, disease-associated PrP) accumulates within cells, and also outside cells in the form of amyloid.

image The accumulated PrPSc is abnormal in that it is relatively resistant to degradation in vitro by proteinase K – this property is the basis of detection of abnormal PrP by immunohistochemical techniques.

image According to the template-directed refolding hypothesis (Fig. 32.4), exogenously added PrPSc serves as a template for the conversion of PrPC into more PrPSc. This conformational change is kinetically controlled in that a high activation-energy barrier prevents spontaneous conversion at detectable rates.

image The seeding (or nucleated crystallization) model (Fig. 32.4) hypothesizes that the conversion is reversible. PrPSc stabilizes when it form a crystal-like seed. Once a seed is formed, further monomers add rapidly.

image Mutations in PrPC increase the likelihood of conversion to PrPSc although as familial TSEs arise quite late in life this presumably remains a relatively rare event. Sporadic CJD may also come about through spontaneous conversion of PrPC to PrPSc, although the likelihood of this occurring is much lower. In both cases the formation of PrPSc initiates a conversion cascade.

Prion strains

Distinct prion strains can be identified with characteristic patterns of CNS pathology and distinct incubation times. Such strains can be stably propagated in experimental animals that are homozygous for their PrP genes (Fig. 32.5).

Differences in the pattern of PrP glycosylation

Research has revealed variations in the pattern of PrP glycosylation in CJD and in spongiform encephalopathies in animals. Western blot analysis of PrP from affected brain tissue shows three bands, corresponding to protein with two, one, or no attached polysaccharide chains (Fig. 32.6).

image

32.6 Glycoforms of PrP and electrophoretic patterns of prion protein in western blots. Left: PrP has two glycosylation sites and can exist in diglycosylated, monoglycosylated and unglycosylated forms. During the conversion to PrPSc, the glycans (glycosylation trees) are preserved. Right: To detect PrPSc in a Western blot, the tissue homogenate (which contains both PrPC and PrPSc) needs to be treated with proteinase K to digest the protease-sensitive PrPC but retain the partially protease resistant PrPSc, leaving a fragment of approximately 142 amino acids. Separation of the ~142-AA fragment by western blotting reveals three bands. The types of PrPSc can be further characterized according to the amino acid – methionine (M) or valine (V) – that is encoded at position 129 in PrP by each of the patient’s two PRPN alleles. The combination of electrophoretic mobility and codon 129 genotyping allows discrimination between different types human of CJD: types 1, 2, 3 or MM1/VV1 and MM2/MV2/VV2 are seen in sporadic CJD, Kuru and iatrogenic CJD, while a distinct, highly characteristic diglycosylation-dominant banding pattern is seen in vCJD, in BSE and other forms where BSE prions were transmitted accidentally or experimentally (type 4 or type MM2B). This diglycosylation-dominant banding pattern is regarded as strong evidence that BSE is the origin of vCJD. Variable glycotype patterns can be found in a single patient. A large, detailed study of 4200 samples from 200 brains showed that two types of PrP coexist in about 35% of sCJD cases. PrPSc types 1 and 2 co-occur more frequently in the MM than in the MV or VV genotypes. These molecular findings correlate to some extent to the histological phenotype. (Adapted from Parchi P, Strammiello R, Notari S, et al. Incidence and spectrum of sporadic Creutzfeldt–Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification. Acta Neuropathol 2009; 118:659–671)

After deglycosylation, the underlying PrP fragment is generally of one of two sizes, running at 19 or 21 kDa. On the basis of size and glycosylation pattern, several types of PrPSc can be distinguished which are associated with different clinical and pathologic patterns of disease.

Prion diseases occur in several mammalian species in addition to man, the most notable being scrapie in sheep and bovine spongiform encephalopathy (BSE) in cattle.

In approximately 85% of cases, human prion diseases are sporadic. Rarely, prion disease is transmitted by accidental inoculation during a therapeutic procedure (iatrogenic CJD), or by endocannibalism (Kuru). In about 15% of cases, prion diseases are inherited in an autosomal dominant fashion.

The commonest phenotype of prion disease is CJD. Patients typically present with subtle motor signs, which herald severe cerebellar ataxia, and progress to global dementia in under 1 year. Criteria for the clinical diagnosis of CJD have been proposed and widely adopted (Table 32.1).

Several phenotypes of prion disease other than CJD have been identified (Table 32.2). In all of these, the mainstay of diagnosis is clinical examination supplemented by additional radiologic, electrophysiologic and neuropathologic investigations (Table 32.3).

Many patients in the late stage of neurodegenerative disease develop myoclonus, but the length of the history usually contrasts with the rapid progression of classic CJD. Some patients who have dementia with cortical Lewy bodies deteriorate rapidly and develop myoclonus, in which case CJD enters the clinical differential diagnosis. The possibility that many cases of dementia of uncertain etiology or dementia with atypical features may be due to undiagnosed prion disease is not supported by comprehensive necropsy studies.

image PRP GENE AND PATHOGENESIS OF PRION DISEASE

Several point mutations and insertions have been identified in the PrP gene that increase the susceptibility of PrP to assume a pathologic conformation (Fig. 32.7).

Nomenclature of PrP gene mutations

This takes the form of disease phenotype (original amino acid, codon position, substituted amino acid), for example GSS (P102L).

Polymorphism at codon 129 acting as a susceptibility factor

In addition to these pathogenic mutations, a polymorphism at codon 129 (which codes for either valine or methionine) acts as a susceptibility factor, modulating the facility with which PrPC assumes an abnormal conformation when interacting with exogenous abnormal PrPP (see below). The frequency of this polymorphism in Caucasian populations is:

In the Japanese population the frequency is:

In studies of the PrP genotype in sporadic CJD, over 90% of cases are homozygous for either M or V at 129, suggesting that this homozygosity confers relative susceptibility to disease. 100% of patients diagnosed with vCJD are MM at codon 129. Having the same amino acid at this position may facilitate conversion of PrPC to PrPP when they interact. In familial disease the clinical and pathological phenotype can be affected by codon 129 (see fatal familial insomnia, below). It remains uncertain whether individuals who are 129 VV or MV will ever develop vCJD and, if they did, whether the clinical pattern of disease would be different from that of the presently characterized 129 MM cases.

image EPIDEMIOLOGY OF CJD

image CJD occurs throughout the world and has an annual incidence of 1–2 cases/million population.

image Higher rates have been recorded in some regions or populations (e.g. Libyan Jews, and in areas of central Slovakia, Hungary, and eastern England). Families with mutations in the prion gene account for these high local rates.

image Approximately equal numbers of men and women are affected.

image About 10% of cases are familial.

image The age of onset is usually 55–75 years with a peak incidence in the 7th decade.

image Rare cases with an onset as young as 16 years or as old as 85 years have been reported.

image Epidemiologic data are largely based on clinical diagnostic criteria. The phenotype is, however, quite variable and these data may not be entirely accurate for all age groups; misdiagnosis is particularly likely in the elderly.

PATHOLOGY

The severity of abnormalities varies. In most cases, the pathologic changes described below are moderate to marked. Rarely, no abnormalities are demonstrable by standard histologic techniques. The neuropathologic manifestations depend upon whether the disease is sporadic, familial, or iatrogenic, and are modified by the nature of the PrP gene defect (if familial) and the codon 129 PrP genotype, and by the duration of the illness.

MACROSCOPIC APPEARANCES

The brain may appear macroscopically normal, even in cases with long clinical histories. Most cases, however, show some atrophy (Fig. 32.8) and this may be severe, with a reduction in brain weight to as low as 850 g. In such cases, ventricular enlargement is marked and the atrophy often includes the caudate nucleus and thalamus. The hippocampus may be relatively spared, even in cases with severe atrophy elsewhere.

Atrophy of the cerebellar folia is common and the brain stem may appear atrophic in some cases. In general, loss of brain substance appears to be confined to the gray matter, and white matter is relatively spared, although this is not always the case (see panencephalopathic CJD, below). Meninges and blood vessels appear normal.

MICROSCOPIC APPEARANCES

The histologic features of prion diseases are:

Spongiform change

Microscopic examination of affected regions of the brain reveals vacuolation of the neuropil, an appearance termed spongiform change (Fig. 32.9). The vacuoles are typically round, relatively small (20–50 μm in diameter), and quite evenly distributed, but some can be large and irregular. The vacuoles are intracellular. Electron microscopy of early lesions shows that most of the vacuoles are within neuronal processes (Fig. 32.10). The vacuolation occurs mainly in gray matter. The distribution of pathology varies greatly between cases. The most consistently affected regions are the cerebral and cerebellar cortices, but the basal ganglia and thalamus are often involved. The distribution of lesions in the cerebral and cerebellar cortices is often patchy, affected regions alternating with seemingly unaffected areas, but may be confluent.

image DIFFERENTIAL DIAGNOSIS OF SPONGIFORM CHANGE IN PRION DISEASES

image Microvacuolation may occur in other diseases and can be confused with the spongiform change of prion disease.

image Status spongiosus (Fig. 32.11) refers to the coarse microvacuolation that accompanies astrocytosis in association with severe neuronal loss. It is a nonspecific finding in several neurodegenerative diseases. It may be part of the pathology of prion disease in some cases, but is not a diagnostic feature.

image Superficial microvacuolation involving layers II and III of the frontal and temporal cortices is a feature of neurodegenerative diseases that present as frontotemporal dementias, especially dementia of frontal type, but also Pick’s disease, dementia with motor neuron disease inclusions, and dementia associated with corticobasal degeneration (Fig. 32.12).

image Dementia with Lewy bodies may be associated with transcortical microvacuolation very similar to that of prion disease (Fig. 32.13). This is localized to medial temporal lobe structures and is not associated with accumulation of PrP.

image Spongiform change in gray and white matter can occur in several metabolic encephalopathies, including aminoaciduria syndromes (Fig. 32.14a), Alpers’ disease, and chronic hepatocerebral degeneration (Fig. 32.14b).

image Microvacuolation can occur in acute hypoxic–ischemic encephalopathy.

image Inadequate fixation or suboptimal processing of brain tissue during paraffin embedding can cause artifactual vacuolation of both gray and white matter.

Hyperphosphorylation of tau

This can occur in response to the cerebral accumulation of amyloid (Aβ in Alzheimer’s disease, ABri and ADan in familial British dementia and familial Danish dementia), and in prion disease. This is particularly prominent in areas of plaque formation but can also be seen in the context of synaptic PrPSc. The deposits are distinct from those seen in Alzheimer’s disease or British dementia, in that neurofibrillary tangles or threads are not formed. PrP-associated tau forms short stubs or rods (Fig. 32.18).

Accumulation of PrP: PrP accumulates in the brain in prion diseases and can be detected by immunohistochemistry. There are several patterns of accumulation:

image a diffuse synaptic pattern (Fig. 32.17)

image perivacuolar deposits (Fig. 32.17)

image larger deposits or plaques (Fig. 32.19) in which some of the PrP may be in the form of amyloid. There are five main types of plaque in prion disease:

• Unicentric plaques, consisting of an amyloid core and radiating spicules of amyloid, which together form a spherical deposit. The amyloid is periodic acid–Schiff (PAS)-positive. This type is often called a kuru plaque.

• Multicentric plaques, consisting of several dense core regions of amyloid with radiating spicules, which form multilobed structures as if made by the fusion of many unicentric plaques. The amyloid is PAS-positive. This form is characteristic of GSS.

• Unicentric plaques, consisting of a dense amyloid core that lacks surrounding radiating spicules of amyloid material. The amyloid is PAS-positive.

• Florid plaques, appearing as unicentric amyloid deposits with radiating spicules of amyloid and a surrounding rim of spongiform change. The amyloid is PAS-positive. This type is characteristic of vCJD.

• Diffuse plaques consisting of large (100–200 μm diameter) ill-defined deposits of PrP that are visible on immunostaining. The deposits are not PAS-positive.

SPORADIC CJD

Several types of CJD can be distinguished on the basis of clinical and neuropathologic criteria. The main patterns of neuronal loss, astrocytosis, and spongiform change in CJD have been categorized as:

It should, however, be emphasized that the distribution of lesions in individual cases may overlap these categories.

Studies have indicated that the characteristics of the disease are partly determined by the human PrP gene (PRNP) codon 129 haplotype (MM, MV, or VV), and also relate to the pattern of PrPP bands on western blotting after limited digestion with proteinase K. The electrophoretic migration, and hence the apparent band size of the resulting amino-terminally truncated cleavage products, varies according to the glycosylation of PrP; the number of attached sugar molecules may be 0, 1, or 2. The presence or absence of Cu– also influences the findings on western blotting. Correlations have been identified between the relative amounts of non-, mono-, or di-glycosylated PrP protein, as evidenced by the density of the corresponding bands in western blots, and the type of CJD. According to one scheme, the two main patterns on western blotting are designated types 1 and 2. Type 2 has been further subdivided into types 2A and 2B, the latter showing a predominance of diglycosylated PrP and being confined to vCJD and BSE (according to another classification scheme, the pattern associated with vCJD is designated type 4). On the basis of the western blot pattern and codon 129 haplotype, several forms of sporadic CJD have been delineated:

image 129MM homozygote and 129MV heterozygote with PrPP type 1 (CJDMM1 and CJDMV1) are common, between them accounting for about 70% of sporadic cases, and characterized by a rapid clinical course, with early dementia, myoclonus, and periodic sharp waves on the EEG. Histologically, there is mild to moderate spongiosis and gliosis in the cerebral cortex, striatum, thalamus, and cerebellar cortex, with general sparing of the brain stem, hippocampus, and hypothalamus. PrP deposition is mainly of the synaptic pattern, in areas of spongiosis.

image 129VV homozygote with PrPP type 2 (CJDVV2) accounts for just under 20% of cases and is characterized by cerebellar signs early in the disease, and late dementia. The deep cerebral nuclei, brain stem, and cerebellum are predominantly affected, with relative sparing of the neocortex. White matter is involved in disease of long duration.

image 129MV heterozygote with PrPP type 2 (CJDMV2) accounts for about 10% of cases and is characterized by both cognitive and cerebellar signs. The deep cerebral nuclei, brain stem, and cerebellum are predominantly affected, with relative sparing of the neocortex. White matter is involved in disease of long duration.

image 129MM homozygote with PrPP type 2 (CJDMM2) is rare and characterized by unusual clinical features. One form corresponds to sporadic fatal insomnia with a thalamic-based pathology, as seen in fatal familial insomnia (see below). Other cases are characterized by a gradual clinical course with dementia but without myoclonus or periodic sharp waves. There is severe neuronal loss with status spongiosus, and PrP deposition is coarse rather than punctate.

image 129VV homozygous with PrPP type 1 (CJDVV1) is very rare and has been reported in only a small number of cases in which there was clinical dementia, with a young age of onset and absence of a typical EEG.

GERSTMANN–STRÄUSSLER–SCHEINKER DISEASE (GSS)

Several clinical conditions are encompassed by the designation GSS, as defined by the presence of multicentric PrP amyloid plaques in the brain (Fig. 32.20):

image Ataxic GSS (PRNP P102L) in which ataxia is combined with varying degrees of dementia. Unicentric and multicentric amyloid plaques are present in the molecular layer of the cerebellar cortex and in smaller numbers in the cerebral cortex. Usually spongiform change is not prominent. The severity of neuronal loss from cerebral and cerebellar cortices is variable.

image Telencephalic GSS (PRNPA117V) in which a dementia syndrome predominates, but ataxia has been the clinical presentation in one family. Multicentric and diffuse plaques are present in neocortical regions and occasionally in the cerebellum. Unicentric amyloid plaques are present in white matter. Spongiform change is absent. Severe neuronal loss and astrocytosis are evident in the basal ganglia and thalamus.

image NFT GSS (PRNPF198S) in which there is a cognitive decline accompanying ataxia, and parkinsonism, is a late feature. Multicentric and unicentric PrP amyloid plaques are seen in the neocortex and cerebellar cortex. There are Aβ plaques and tau-immunoreactive neurofibrillary tangles in a distribution compatible with early Alzheimer’s disease. Plaques with combined Aβ and PrP immunoreactivities are a rare finding. Neuronal loss affects the neocortex and cerebellar cortex. (Tangles may be seen in other familial cases PRNP Q217R, PRNP Y145*, and some cases with PRNP P105L and PRNP A117V.)

image Progressive spastic paraparesis GSS (PRNPP105L) in which a clumsy hand is an early feature. This is followed by gait disturbance, spastic paraparesis, and ataxia. Cognitive decline and dysarthria are late features. No spongiform change is seen. Plaques occur mainly in the cerebral cortex with less involvement of the cerebellum and basal ganglia.

image GSS (PRNPY145*) produces a slowly progressive dementia. The histology is characterized by blood vessel-related amyloid plaques. Tangles and neuropil threads may be seen in the cerebral cortex.

image GSS (PRNP octapeptide repeat), in which ataxia precedes dementia. Cerebellar plaques are found, with less involvement of the cerebral cortex. Spongiform change is present.

FATAL FAMILIAL INSOMNIA (FFI)

FFI is due to a PRNP D178N (aspartic acid to asparagine) mutation in association with a methionine residue at codon 129. The pathologic features are:

The phenotype caused by the D178N mutation in PRNP is modified by the non-pathogenic polymorphism found at codon 129.

It is believed that the 129 polymorphism has an effect on the rate of accumulation of the PrPP isoform.

VARIANT CJD (VCJD)

vCJD has a distinct neuropathological profile. The cerebral cortex and cerebellum typically contain numerous amyloid plaques which are distinct from those in Kuru or inherited forms of prion disease (Fig. 32.21). Many plaques are surrounded by vacuoles and have been termed florid plaques (Fig. 32.22). Spongiform change, neuronal loss, and astrocytic gliosis are generally very severe and are most evident in the thalamus and basal ganglia. Within the CNS, immunohistochemistry typically shows an abundant accumulation of PrP (Fig. 32.23). Additionally, and in remarkable contrast to all other forms of prion diseases, there is accumulation of PrPSc in lymphoreticular tissues such as the tonsil, lymph nodes, spleen, and appendix (Fig. 32.23). This finding is unique to vCJD and has not been observed in sporadic, inherited or, importantly, in acquired prion diseases in which human prions were transmitted (i.e. iatrogenic forms and Kuru). This unique property of the vCJD strain allows pre-mortem diagnosis of vCJD by tonsil biopsy. PrPSc can be demonstrated in follicular dendritic cells of lymphoid tissue by immunohistochemistry.

On western blotting, vCJD brain or tonsil samples partially digested with proteinase K show a distinctive (type 4) pattern of PrP immunolabeling, due to the high proportion of diglycosylated PrPSc (the pattern produced on western blotting of tonsillar tissue is slightly different from that of brain and has been designated 4 t). A type 4 pattern is also produced by extracts from brains of BSE-infected cattle, zoo or pet animals and experimentally infected mice. Taken together with the results of other biological studies, these findings provide very strong evidence that vCJD and BSE are caused by the same strain of agent.

Between 1994 and 2012, more than 170 people in the UK and more than 220 people worldwide developed clinical vCJD. The number of subclinically infected individuals remains uncertain. Up to 2011, four instances of vCJD infection resulting from transfusion of blood from infective but asymptomatic people had been reported.

IATROGENIC CJD

Iatrogenic CJD has been transmitted mainly by intramuscular administration of hormones (growth hormone or gonadotropin) derived from human cadaveric pituitary glands. The risk of contracting CJD to patients who received human growth hormone is estimated at approximately 1:200. Many of the UK pituitary hormone recipients who have developed iatrogenic CJD have been homozygous for valine at codon 129, but this has not been the case in all other countries. Disease has also been transmitted from human tissue grafts (cornea and dura) and through the use of surgical instruments contaminated by infected brain tissue.

In this variant, patients tend to present with a cerebellar syndrome and only later develop dementia.

There are typically widespread neuronal loss and spongiform change in the cerebellar cortex and to a lesser degree in the cerebral cortex (Fig. 32.24). Plaques are common. PrP immunohistochemistry reveals heavy deposits in the cerebellum and a linear pattern of labeling involving the deeper laminae of the cerebral cortex.

PANENCEPHALOPATHIC CJD

The panencephalopathic form of CJD is characterized by extensive involvement of white matter as well as cerebral cortex (Fig. 32.25). It has been suggested that this is an end-stage pattern that reflects relatively prolonged disease.

The brain generally shows severe atrophy. Marked neuronal loss and spongiform change in the cerebral cortex are associated with an intense astrocytosis. There is diffuse myelin pallor in the hemispheric white matter, which appears spongy and may become cavitated. These changes are accompanied by moderate astrocytosis and an accumulation of lipid in macrophages (Fig. 32.25).

The basal ganglia and thalamus show severe neuronal loss and spongiform change with gliosis. The cerebellar granular cell layer is markedly depleted of neurons and the molecular layer correspondingly atrophic. Purkinje cells are relatively well preserved. The spinal cord shows distal degeneration of corticospinal tracts.

KURU

Kuru exemplifies an epidemic human prion disease, which predominantly affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea and to a lesser extent, neighboring groups. It is hypothesized that Kuru originated from chance consumption of an individual with sporadic CJD. It was the practice in these communities to engage in consumption of dead relatives as a mark of respect and mourning.

Kuru was the first human prion disease shown to be transmissible, by inoculation of non-human primates with autopsy-derived brain tissue.The hypothesized pathogenesis is supported by the fact that Kuru prions have molecular strain types and transmission properties equivalent to those of classical CJD prions rather than vCJD prions or inherited forms of prion disease.

Clinical presentation and the neuropathology of Kuru are distinct from the majority of patients with sporadic CJD, in that Kuru presents with progressive cerebellar ataxia. Dementia is a late and less prominent feature. In contrast to vCJD there is no accumulation of abnormal PrP in lymphoreticular tissue (Fig. 32.26).

image NECROPSY AND DECONTAMINATION PROCEDURES

Necropsy for the diagnosis of CJD can be carried out safely in a standard mortuary, but the following precautions should be taken

PITFALLS IN THE HISTOPATHOLOGICAL DIAGNOSIS OF PRION DISEASE

The diagnosis of prion diseases by examination of brain biopsies can be complicated by a number of pitfalls, some related to technical difficulties associated with PrP immunostaining, others to the biochemical properties of PrPC. See Figure 32.27 for details.

image

32.27 (1) Insufficient suppression of the cellular form PrPC. Most PrP antibodies detect non-denatured PrPC as well as PrPSc. Immersion of the deparaffinized section in concentrated formic acid is essential to denature PrPC and reduce this staining. The staining pattern of insufficiently denatured PrPC is smooth and regular (a), similar to that of synaptophysin, and lacking the granularity of synaptic PrPSc deposits; (2) Entrapment of PrPC into amyloid beta plaques. Aβ plaques (b) entrap a multitude of proteins, including prion protein. Formic acid denaturation does not eliminate this staining, possibly because of intercalation of PrP into the β-pleated sheet structure of the plaques (c). A similar phenomenon can also occasionally be observed in the context of diffuse Aβ deposits; (3) Entrapment of PrPC by other structures. PrPC can be entrapped within neurofibrillary tangles. Occasionally, neurons that do not show morphological feature of tangles label with some PrP antibodies (d). Such structures may represent neurons with pre-tangle tau but this remains speculative; (4) Accumulation of PrP in the perivascular space. Perivascular dense granular or small globular deposits of PrP are sometimes labeled in Virchow-Robin spaces around small cortical vessels. Unlike Aβ peptides (typically Aβ40), this form of PrP does not deposit in the vessel walls (e). Unpublished observations suggest that chronic heart and liver failure are associated with these perivascular accumulations of PrP; (5) Entrapment of Aβ within prion protein plaques. This is an important pitfall if the clinical presentation does not suggest a prion disease and the pathologist has performed immunohistochemistry for abnormal PrP. Knowledge of the different plaque morphologies in Alzheimer’s and prion diseases is essential.

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