The transmissible spongiform encephalopathies (TSEs) or prion diseases are a group of neurodegenerative disorders which include kuru (1), Creutzfeldt-Jakob disease (CJD) (2), Gerstmann-Sträussler-Scheinker (GSS) disease (3), and fatal familial insomnia in man (4, 5) natural scrapie in sheep, goats (6-9), and mufflons (10), transmissible mink encephalopathy in ranch-reared mink (11), chronic wasting disease of deer, elk and moose in the USA and Canada (12-16), bovine spongiform encephalopathy or "mad cow disease” (17) and its analogues in several exotic species of antelopes (18-21), and wild felids in Zoological gardens (22), and feline spongiform encephalopathy in domestic cats (23).

These disorders are caused by a still not completely understood pathogen variously referred to as a "prion” or a slow, unconventional or atypical virus, or "virino” (24-27). Despite wide acceptance for the prion theory, these designations still reflect different views about the real molecular structure of the pathogen and, by the same token, our ignorance of its nature. Those who prefer to view this pathogen as composed "predominantly or exclusively” of a pathologically folded (misfolded) protein (PrP^res, PrP^Sc; Sc, from scrapie or PrP^d; d, from disease; PrP^TSE, TSE from transmissible spongiform encephalopathy), use the term "prion” (28-31); hence the term "prion diseases” (25, 32, 33).

In 1995 Budka et al. (34) published a set of criteria to diagnose human TSEs on the basis of classical neuropathological staining and immunohistochemistry.

1. Creutzfeldt-Jakob disease

1.1. Spongiform encephalopathy in cerebral/or cerebellar cortex and/or subcortical gray matter

1.2. Encephalopathy with PrP immunoreactivity (plaque and/or diffuse synaptic and/or patchy/perivacuolar types)

2. Gerstmann-Sträussler-Scheinker disease (GSS). Encephalomyelopathy with multicentric PrP plaques

3. Fatal familial insomnia. Thalamic degeneration with focal cerebral spongiform change

4. Kuru (in the Fore population of New Guinea)

sCJD is a disease of the elderly, however, the number of deaths in persons over age 70 and higher is gradually rising. In the early 1970s, it was around 1 per year and in recent days, it is around 30 per year (35). Furthermore, the meadian ages of cases during time periods 1970-89, 1990-95 and 1996-2008 also increased from 64 years, through 66 years to 68 years, respectively. A short inquiry performed for the purpose of this review revealed that in the Austrian database, there were 17 cases between 70-75 years old; 10 cases: 76-79 years old; 11 cases 80-85 years old but only 1 case 86 years old. In the Netherlands, out of a total of 150 CJD patients for years 1998-2008, they were 39 cases between 70 and 75 years of age (or 28 if age 70 is not included); 15 cases: 76-79 years of age; 9 cases: 80-85 years of age but non for 86 year of age or older. In the UK, 42% of 1089 sCJD patients were aged 70 or over at death during the period May 1990-November 2009, comprising 33% of sCJD cases aged 70-79 and 9% of cases aged 80 or over (fig. 1). Analysis of the codon 129 polymorphism in the prion protein gene ( PRNP) in the UK sCJD cases found overall 63% were methionine homozygotes (MM), 18% were valine homozygotes (VV) and 19% were heterozygotes (MV). In the cases aged 70 or over at death, the distribution was 68% MM, 16% VV and 16% MV.

The Polish data are very interesting in this respect: there are 6 of 30 cases of sCJD over 70 (20%); the 129 codon data are available for 3, 2 x MM, 1 x MV.

The literature on the subject of this review is very limited.

De Silva and colleagues (36) reviewed 12 cases over 80 years of age and added a case of 86-year-old CJD patient. The duration of disease for those 12 cases ranged between 1 and 5 months, the EEG showed PSWCs in 6 cases but was atypical in another six, and they presented as rather typical sCJD. The 86-year-old age case presented with disorientation and self-neglect, jerky limb movement and on EEG, slow background rhythms and periodic complexes. Terminally, she had frontal release signs. Neuropathological examination revealed spongiform change and immunoexpression of PrP^Sc.

The oldest case was published by Buganza et al. (37). This was a 98-year-old patient admitted to the hospital because of an ataxic gait of 10 days duration. The following day – myoclonic jerks were observed, followed by – generalized seizures. The EEG revealed continued seizure activity turned into periodic sharp wave complexes (PSWCs), otherwise typical for CJD. Western blot analysis revealed type 1 PrP^Sc, and molecular analysis revealed that the patient was a Methionine homozygote at the 129 codon of the PRNP gene. Neuropathological examination showed widespread spongiform change and diffuse PrP-immunoexpression.

There are several points to be raised by those very limited observations. First, all those cases presented as typical sCJD. The only possible exception is generalized seizures in the case of Buganza et al. (37). Of note, Collins et al. (38) described a case of 82-year-old woman who also presented with generalized seizures. However, that case was not only a methionine homozygote, but also a carrier of T188A mutation. Thus, it is tempting to speculate that seizures may be a sign of CJD in the elderly.

Those old CJD cases are also interesting from a pathogenetic perspective. According to the prion theory, sCJD may be caused by a stochastic event of a change of a normal PrP isoform into its pathologic counterpart. However, if this is really a stochastic event, it should be time-dependent, thus the number of sCJD cases should increase with age and definitively the reverse is observed (fig. 2-3), the number of sCJD cases in – old age is small.

Variant CJD (vCJD) is worthy of separate consideration. vCJD is caused by a passage of BSE from bovine to humans and occurs in younger patients. However, Lorains et al. (39) described a unique vCJD case in a 74-year-old patient. He presented to the hospital with psychiatric symptoms, visual hallucinations and delusions of 1 month duration. His cognitive state declined, and he died with bilateral bronchopneumonia. At autopsy, abundant florid plaques, typical for vCJD were found in the brain and widespread PrP^Sc immunoreactivity was detected. As – for all definite vCJD cases this case was a methionine homozygote at codon 129 in the PRNP gene.

It is worthy to analyse those cases against a current sCJD classification based on the codon 129 status and the species of PrP^Sc (type 1 or 2 based on N-terminal cleavage site). Based on analysis of some 300 cases of sCJD, Parchi and colleagues (40), described 6 subtypes of sCJD that differ in some fundamental characteristics:

? MM1/MV1 or myoclonic/Heidenhain variants; age of onset 65.5 (42-91) for MV1 and age of onset 62.1 (51-72), for MV1

? VV2 – ataxic (or Betty Bronwell) variant; age of onset 61.3 (41-80)

? MV2 – kuru plaque variant, age of onset 59.4 (40-81)

? MM2-thalamic – thalamic variant or FFI, age of onset 52.3 (36-71)

? MM2-cortical, age of onset 64.3 (49-77)

? VV1, age of onset 39.3 (24-49)

This data clearly showed, that sCJD at the age over 70 may be seen in practically every subtype except perhaps the VV1 sCJD subtype; the classical MM1 and MV2 sCJD subtypes included cases of the highest age of onset (91 and 81, respectively), followed by MV1 classical sCJD variant (80 year at the onset). In the UK, the MM1 sCJD subtype was the commonest in all ages, including those aged 70 or over at death (fig. 4). This elderly group included all the recognised sCJD subtypes, including the rare VV1 subtype, cases with mixed PrP isoforms in all PRNP codon 129 genotypes and a case of the recently reported protease sensitive prionopathy (PSPr) (41, 42).