Late-Onset Metachromatic Leukodystrophy with Early Onset Dementia Associated with a Novel Missense Mutation in the Arylsulfatase A Gene.

A 48-year-old male patient presented with personality changes and progressive memory loss over 2 years with initially suspected Hashimoto's encephalopathy. Strategy of diagnostic workup of early onset dementia included dementia from neurodegenerative, neuroinflammatory, metabolic/toxic, and psychiatric origin. The patient's neurological exam was normal. MRI revealed a leukencephalopathy, predominantly in the frontal periventricular white matter, without notable changes over 2 years. On neurophysiological examination, prolonged central conduction times and a sensorimotor polyneuropathy were noted. Neuropsychological impairment included disorientation in place and a reduced short time memory. Behavioral alterations were predominated by sudden mood changes and disinhibition. Cerebrospinal fluid was normal. Despite presence of thyroid autoantibodies, glucocorticosteroid treatment did not improve the dementia. A metachromatic leukodystrophy was diagnosed by decreased arylsulfatase-A activity in leucocytes/fibroblasts and identification of a compound heterozygous mutation in the ARSA gene: c.542T>G (exon 3) and the novel mutation c.1013T>C (exon 6). Pathogenic function was suggested by bioinformatic mutation search. In a patient with early onset dementia, strategic diagnostic workup including genetic assessment revealed an adult-onset metachromatic leukodystrophy with a novel mutation in the arylsulfatase A gene.

Comparative analysis of cerebrospinal fluid biomarkers in the differential diagnosis of neurodegenerative dementia.

INTRODUCTION: The analysis of cerebrospinal fluid biomarkers gains importance in clinical routine and is effective in substantiating dementia diagnosis in the differential diagnostic context. METHODS: We evaluated the levels of ß-amyloid (Aß) 42, Aß40, tau, and P-tau in a large patient population subdivided into prion diseases, tauopathies, synucleinopathies, and controls. Diagnostic test evaluation was assessed by ROC area under the curve analysis. RESULTS: High tau levels were detected in sporadic Creutzfeldt-Jakob disease (sCJD) and high P-tau levels in Alzheimer's disease (AD) and sCJD. Aß40 was lower exclusively in prionopathies, but low Aß42 was detected in AD, sCJD, and Lewy body dementia. When disease groups were stratified according to the underlying proteinopathy, we detected disease-type specificities for all biomarkers. P-tau/tau, Aß42/40, Aß42/tau, and Aß40/tau ratios proved valuable in discriminating disease groups and controls, especially P-tau/tau ratio in the identification of sCJD cases. DISCUSSION: Combining the biomarker panel allows differentiating between various types of neurodegenerative dementias and contributes to a better understanding of their pathophysiological processes.

Validation of 14-3-3 Protein as a Marker in Sporadic Creutzfeldt-Jakob Disease Diagnostic.

At present, the testing of 14-3-3 protein in cerebrospinal fluid (CSF) is a standard biomarker test in suspected sporadic Creutzfeldt-Jakob disease (sCJD) diagnosis. Increasing 14-3-3 test referrals in CJD reference laboratories in the last years have led to an urgent need to improve established 14-3-3 test methods. The main result of our study was the validation of a commercially available 14-3-3 ELISA next to the commonly used Western blot method as a high-throughput screening test. Hereby, 14-3-3 protein expression was quantitatively analyzed in CSF of 231 sCJD and 2035 control patients. We obtained excellent sensitivity/specificity values of 88 and 96% that are comparable to the established Western blot method. Since standard protocols and preanalytical sample handling have become more important in routine diagnostic, we investigated in a further step the reproducibility and stability of 14-3-3 as a biomarker for human prion diseases. Ring trial data from 2009 to 2013 revealed an increase of Fleiss' kappa from 0.51 to 0.68 indicating an improving reliability of 14-3-3 protein detection. The stability of 14-3-3 protein under short-term and long-term storage conditions at various temperatures and after repeated freezing/thawing cycles was confirmed. Contamination of CSF samples with blood appears likely to be an important factor at a concentration of more than 2500 erythrocytes/µL. Hemolysis of erythrocytes with significant release of 14-3-3 protein started after 2 days at room temperature. We first define clear standards for the sample handling, short- and long-term storage of CSF samples as well as the handling of blood- contaminated samples which may result in artificially elevated CSF levels of 14-3-3.

Cytokine profiles and the role of cellular prion protein in patients with vascular dementia and vascular encephalopathy.

Understanding inflammatory mechanisms in vascular dementia (VD) is pivotal for achieving better insights into changes in brain metabolism. We performed cytokine profiling and measured levels of the cellular prion protein (PrP(C)) in serum and cerebrospinal fluid (CSF) samples from patients with VD and with vascular encephalopathy (VE). Significant changes were observed for interleukin (IL)-1ß, IL-4, IL-5, tumor necrosis factor alpha, interferon gamma, granulocyte-colony stimulating factor, monocyte chemotactic protein 1, and macrophage inflammatory protein 1 beta in serum and for IL-6 and granulocyte macrophage colony-stimulating factor in CSF of VD and VE patients, suggesting that most of immune markers depend on vascular lesions, while only IL-6 was related to dementia. In VD patients, the severity of dementia as defined by the Mini-Mental Status Test or Cambridge Cognitive Examination battery test was significantly correlated with the levels of IL-8 (CSF) and macrophage inflammatory protein 1 beta (serum and CSF). Additionally, in CSF of VD patients, our data revealed a correlation between immune and neurodegenerative marker proteins. Both indicate an association of neuroinflammation and cognitive decline. Levels of PrP(C) were regulated differentially in VD and VE patients compared with Alzheimer's disease patients and controls. Moreover, we observed a significant negative correlation between cytokine levels and PrP(C) in VD patients in CSF and serum, as well as a correlation between PrP(C) expression with levels of neurodegenerative marker proteins in CSF (in VD and VE patients). Our data suggest that immunological modifiers play a role in VD and VE patients and provide evidence for an association of PrP(C) with immune and neurodegenerative markers.

Immune responses in rapidly progressive dementia: a comparative study of neuroinflammatory markers in Creutzfeldt-Jakob disease, Alzheimer's disease and multiple sclerosis.

Immunological responses may contribute to disease progression and clinical heterogeneity in neurodegenerative dementia, for example, Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD). Recently, a rapidly progressive form of AD (rpAD) has been described. On neuropathological grounds classical AD and rpAD are not distinguishable at present. All those protein aggregopathies show a state of chronic inflammation with microglia activation and production of proinflammatory cytokines. In this context, it is hypothesized that the severity of the surrounding inflammation substantially contributes to disease progression and accelerated disease courses as seen in rpAD.

Using cerebrospinal fluid marker profiles in clinical diagnosis of dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease.

BACKGROUND: Dementia with Lewy bodies (DLB) is difficult to differentiate from other neuro-degenerative diseases. Patients are often mistaken to suffer from Parkinson's disease (PD) or Alzheimer's disease (AD) because of the overlapping clinical appearances concerning cognition and movement. OBJECTIVE: We investigated the possibility for a valid differential diagnosis using cerebrospinal fluid (CSF) biomarkers. METHODS: In the context of a large retrospective study, we analyzed data of patients suffering from degenerative, ischemic, or inflammatory CNS (central nervous system) diseases and identified those with DLB (n = 34), PD (n = 37), and AD (n = 47) for further analyses. RESULTS: We detected abnormalities in the CSF profiles of those patients with DLB while using a combination of decreased amyloid-ß (Aß)42 and increased tau levels. By stratification of data by disease severity, we observed a high sensitivity of this combination especially in the subgroup of patients with advanced stages, while the sensitivity in early forms was lower. In addition, with clinical deterioration, the abnormalities in the CSF profile became more pronounced. CONCLUSION: We conclude that DLB can be distinguished from PD, in spite of both being synucleinopathies, by CSF profiles using neurodegenerative marker analysis. The pathophysiology of increased tau and decreased Aß levels in those conditions has to be elucidated further, since both proteins are known to be involved in the pathogenesis of AD, but no clear explanation has been postulated for DLB yet.

Cerebrospinal fluid biomarkers in Alzheimer's disease, vascular dementia and ischemic stroke patients: a critical analysis.

Vascular factors are thought to contribute to the development of disease pathology in neurodegenerative dementia such as Alzheimer's disease (AD). Another entity, called vascular dementia (VaD), comprises a less defined group of dementia patients having various vascular diseases that especially emerge in the elderly population and require valid options for examination and differential diagnosis. In the context of a retrospective study, we analyzed the cerebrospinal fluid (CSF) biomarkers t-tau, p-tau and Aß42 of a total of 131 patients with AD (n = 47), mild cognitive impairment (MCI) (n = 22), VaD (n = 44) and stroke (n = 18). We found a remarkable alteration in CSF biomarker profile in AD, VaD and in acute ischemic events. CSF profile in AD patients was altered in a very similar way as in stroke patients, without statistical differences. In stroke, increase depend largely on size and duration after the initial event. Total tau levels were useful to differ between VaD and stroke. Aß42 decreased in a similar way in AD, VaD and stroke and had a trend to lower levels in MCI but not in controls.

Report about four novel mutations in the prion protein gene.

BACKGROUND/AIMS: Since detection of the prion protein gene (PRNP) more than 30 mutations have been discovered. Some have only been found in single case reports without known intrafamilial accumulation or neuropathological proof so that the causal connection between mutation and disease could not be proved. Those patients often present atypical clinical phenotypes, and it is not unusual that they are classified as diseases other than Creutzfeldt-Jakob disease (CJD). METHODS: Cases of suspected CJD have been reported to the national reference center for prion diseases. Clinical and diagnostic data were collected, and a classification of definite, possible or probable prion disease was made. Molecular analysis of PRNP was performed by capillary sequencing. RESULTS: We have described 4 cases with atypical clinical and diagnostic findings and unknown mutations in PRNP so far. CONCLUSION: Three patients fulfilled the criteria of probable CJD, and 1 patient fulfilled the criteria of possible CJD but the clinical picture in none of the patients was typical CJD; hence, it remained questionable whether the mutations were causal of the disease.

Cerebrospinal fluid biomarker supported diagnosis of Creutzfeldt-Jakob disease and rapid dementias: a longitudinal multicentre study over 10 years.

To date, cerebrospinal fluid analysis, particularly protein 14-3-3 testing, presents an important approach in the identification of Creutzfeldt-Jakob disease cases. However, one special point of criticism of 14-3-3 testing is the specificity in the differential diagnosis of rapid dementia. The constant observation of increased cerebrospinal fluid referrals in the national surveillance centres over the last years raises the concern of declining specificity due to higher number of cerebrospinal fluid tests performed in various neurological conditions. Within the framework of a European Community supported longitudinal multicentre study ('cerebrospinal fluid markers') we analysed the spectrum of rapid progressive dementia diagnoses, their potential influence on 14-3-3 specificity as well as results of other dementia markers (tau, phosphorylated tau and amyloid-ß(1-42)) and evaluated the specificity of 14-3-3 in Creutzfeldt-Jakob disease diagnosis for the years 1998-2008. A total of 29 022 cerebrospinal fluid samples were analysed for 14-3-3 protein and other cerebrospinal fluid dementia markers in patients with rapid dementia and suspected Creutzfeldt-Jakob disease in the participating centres. In 10 731 patients a definite diagnosis could be obtained. Protein 14-3-3 specificity was analysed for Creutzfeldt-Jakob disease with respect to increasing cerebrospinal fluid tests per year and spectrum of differential diagnosis. Ring trials were performed to ensure the comparability between centres during the reported time period. Protein 14-3-3 test specificity remained high and stable in the diagnosis of Creutzfeldt-Jakob disease during the observed time period across centres (total specificity 92%; when compared with patients with definite diagnoses only: specificity 90%). However, test specificity varied with respect to differential diagnosis. A high 14-3-3 specificity was obtained in differentiation to other neurodegenerative diseases (95-97%) and non-neurological conditions (91-97%). We observed lower specificity in the differential diagnoses of acute neurological diseases (82-87%). A marked and constant increase in cerebrospinal fluid test referrals per year in all centres did not influence 14-3-3 test specificity and no change in spectrum of differential diagnosis was observed. Cerebrospinal fluid protein 14-3-3 detection remains an important test in the diagnosis of Creutzfeldt-Jakob disease. Due to a loss in specificity in acute neurological events, the interpretation of positive 14-3-3 results needs to be performed in the clinical context. The spectrum of differential diagnosis of rapid progressive dementia varied from neurodegenerative dementias to dementia due to acute neurological conditions such as inflammatory diseases and non-neurological origin.

Cellular immune activation markers neopterin and ß2-microglobulin are not elevated in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.

In prion diseases, neuroimmunological responses include activation of microglia, astrocytosis and release of pro- and anti-inflammatory cytokines, which might substantially contribute to the neurodegenerative process. In this study we investigated neopterin and beta(ß)2-microglobulin, as markers of cellular immune activation, in the cerebrospinal fluid (CSF) of patients with Creutzfeldt-Jakob disease (CJD) and of patients with other neurological and non-neurological diseases. CSF samples from CJD patients were collected in the framework of the German CJD Surveillance study. Concentrations of neopterin and ß2-microglobulin were determined in CSF using ELISA. We could not obtain significant changes in CSF levels of neopterin and ß2-microglobulin in CJD patients when compared to other neurological and non-neurological controls. In a subanalysis of CJD patients only, we could find significant elevated neopterin levels in patients with MV genotype, potentially reflecting a distinct disease pathology. Since autoimmune inflammatory disorders are important differential diagnoses in CJD, additional biomarker might be helpful in clinical setting.

A case-control study of sporadic Creutzfeldt-Jakob disease in Switzerland: analysis of potential risk factors with regard to an increased CJD incidence in the years 2001-2004.

BACKGROUND: In 2001, the observed annual mortality from Creutzfeldt-Jakob disease (CJD) in Switzerland increased from less than 1.5 to 2.6 per million inhabitants. An underlying cause could not be identified. METHODS: To analyse potential risk factors for sCJD in Switzerland, close relatives of 69 sCJD-patients and 224 frequency age-matched controls were interviewed in a case-control study using a standardised questionnaire. 135 potential risk factors including socio-demographics, medical history, occupation and diet were analysed by logistic regression adjusting for age, sex and education. RESULTS: sCJD patients were more likely to have travelled abroad, worked at an animal laboratory, undergone invasive dental treatment, orthopaedic surgery, ophthalmologic surgery after 1980, regular GP visits, taken medication regularly, and consumed kidney. No differences between patients and controls were found for residency, family history, and exposure to environmental and other dietary factors. CONCLUSION: Although some factors were significantly more frequent among sCJD-cases, this study did not reveal specific explanations for the increased incidence of deaths due to sporadic CJD observed in Switzerland since 2001. Results have to be interpreted with caution due to multiple testing and possible recall bias in association with a long incubation period. The most plausible reason for the increase in Swiss sCJD cases after 2000 is an improved case ascertainment. Therefore, underreporting of cases might well have occurred before the year 2001, and the "real" yearly incidence of sCJD might not be lower than, but rather above 2 per million inhabitants.

Urinary alpha1-antichymotrypsin: a biomarker of prion infection.

The occurrence of blood-borne prion transmission incidents calls for identification of potential prion carriers. However, current methods for intravital diagnosis of prion disease rely on invasive tissue biopsies and are unsuitable for large-scale screening. Sensitive biomarkers may help meeting this need. Here we scanned the genome for transcripts elevated upon prion infection and encoding secreted proteins. We found that alpha(1)-antichymotrypsin (alpha(1)-ACT) was highly upregulated in brains of scrapie-infected mice. Furthermore, alpha(1)-ACT levels were dramatically increased in urine of patients suffering from sporadic Creutzfeldt-Jakob disease, and increased progressively throughout the disease. Increased alpha(1)-ACT excretion was also found in cases of natural prion disease of animals. Therefore measurement of urinary alpha(1)-ACT levels may be useful for monitoring the efficacy of therapeutic regimens for prion disease, and possibly also for deferring blood and organ donors that may be at risk of transmitting prion infections.

Heightened incidence of sporadic Creutzfeldt-Jakob disease is associated with a shift in clinicopathological profiles.

Incidences of human transmissible spongiform encephalopathies are monitored by national registries in the majority of countries in Western Europe. During the past 13 years incidences for Creutzfeldt-Jakob disease (CJD) in Switzerland fluctuated between 0.4 and 2.63 cases/10(6) inhabitants. We have compared clinicpathological patient profiles including geographic and gender distribution, age at disease onset, duration of disease, clinical symptoms, and recognized or hypothetical risk factors for CJD, genetic risk factors, biochemical and histopathological data for two cohorts of Swiss sporadic CJD patients from years of regular sporadic CJD incidence (1996-2000, mean incidence 1.3 cases/10(6) inhabitants, n = 47) to Swiss sporadic CJD patients from years of elevated sporadic CJD incidence (2001-2004, mean incidence 2.3 cases/10(6) inhabitants, n = 73). Sporadic CJD patients from the cohort with elevated sporadic CJD incidence presented with a higher frequency of rare sporadic CJD subtypes. Patients of these subtypes were significantly older and showed a skewed male/female ratio when compared to published patients of identical sporadic CJD-types or to patients from the 1996-2000 cohort and indicates that improved detection of rare sporadic CJD subtypes may have contributed to increased incidence.

Human transmissible spongiform encephalopathies in eleven countries: diagnostic pattern across time, 1993-2002.

BACKGROUND: The objective of this study was to describe the diagnostic panorama of human transmissible spongiform encephalopathies across 11 countries. METHODS: From data collected for surveillance purposes, we describe annual proportions of deaths due to different human transmissible spongiform encephalopathies in eleven EUROCJD-consortium countries over the period 1993-2002, as well as variations in the use of diagnostic tests. Using logistic models we quantified international differences and changes across time. RESULTS: In general, pre-mortem use of diagnostic investigations increased with time. International differences in pathological confirmation of sporadic Creutzfeldt-Jakob disease, stable over time, were evident. Compared to their counterparts, some countries displayed remarkable patterns, such as: 1) the high proportion, increasing with time, of variant Creutzfeldt-Jakob disease in the United Kingdom, (OR 607.99 95% CI 84.72-4363.40), and France (OR 18.35, 95% CI 2.20-152.83); 2) high, decreasing proportions of iatrogenic Creutzfeldt-Jakob disease in France, (OR 5.81 95% CI 4.09-8.24), and the United Kingdom, (OR 1.54 95% CI 1.03-2.30); and, 3) high and stable ratios of genetic forms in Slovakia (OR 21.82 95% CI 12.42-38.33) and Italy (OR 2.12 95% CI 1.69-2.68). CONCLUSION: Considerable international variation in aetiological subtypes of human transmissible spongiform encephalopathies was evident over the observation period. With the exception of variant Creutzfeldt-Jakob disease and iatrogenic Creutzfeldt-Jakob disease in France and the United Kingdom, these differences persisted across time.

Pro- and anti-inflammatory cytokines in the CSF of patients with Creutzfeldt-Jakob disease.

We investigated cerebrospinal fluid (CSF) samples from patients with Creutzfeldt-Jakob disease (CJD) and other neurological diseases. Concentrations of pro- and anti-inflammatory cytokines IL-1beta, IL-6, IL-8, IL-12, TNF-alpha and TGF-beta 2 were determined in CSF using ELISA. Significant changes were found for IL-8 and TGF-beta 2. IL-8 levels were elevated in the CSF of CJD patients. Of interest, the increase was significant to other dementia and to controls. In contrast, TGF-beta 2 was significantly decreased in CSF of CJD compared to all groups. IL-1beta, IL-12 and TNF-alpha could not be detected in CSF or in case of IL-6 in only low concentrations without significant difference.

Coexistence of multiple PrPSc types in individuals with Creutzfeldt-Jakob disease.

BACKGROUND: The molecular typing of sporadic Creutzfeldt-Jakob disease (CJD) is based on the size and glycoform ratio of protease-resistant prion protein (PrP(Sc)), and on PRNP haplotype. On digestion with proteinase K, type 1 and type 2 PrP(Sc) display unglycosylated core fragments of 21 kDa and 19 kDa, resulting from cleavage around amino acids 82 and 97, respectively. METHODS: We generated anti-PrP monoclonal antibodies to epitopes immediately preceding the differential proteinase K cleavage sites. These antibodies, which were designated POM2 and POM12, recognise type 1, but not type 2, PrP(Sc). FINDINGS: We studied 114 brain samples from 70 patients with sporadic CJD and three patients with variant CJD. Every patient classified as CJD type 2, and all variant CJD patients, showed POM2/POM12 reactivity in the cerebellum and other PrP(Sc)-rich brain areas, with a typical PrP(Sc) type 1 migration pattern. INTERPRETATION: The regular coexistence of multiple PrP(Sc) types in patients with CJD casts doubts on the validity of electrophoretic PrP(Sc) mobilities as surrogates for prion strains, and questions the rational basis of current CJD classifications.

Interleukin 4 and interleukin 10 levels are elevated in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease.

BACKGROUND: In neurodegenerative diseases, increasing attention has been focused on inflammatory mediators such as pro-inflammatory and anti-inflammatory cytokines and their potential influence in the process of neurodegeneration. In prion diseases, much data has been gained on the cell culture and animal disease models level, but only limited information is available on humans affected by Creutzfeldt-Jakob disease (CJD). OBJECTIVE: To obtain data on anti-inflammatory cytokines interleukin 4 and interleukin 10 in the cerebrospinal fluid of patients with CJD, patients with other dementia, and nondemented neurological patients and controls. DESIGN: Cerebrospinal fluid samples were collected from CJD patients and control subjects, and concentrations of the anti-inflammatory cytokines interleukin 4 and interleukin 10 were determined using an enzyme-linked immunosorbent assay. PATIENTS: Cerebrospinal fluid samples from 61 patients were analyzed. The group was composed of patients with CJD (n = 20), patients with other forms of dementia (n = 10), patients with motoneuron disease (n = 6), patients with normal pressure hydrocephalus (n = 5), and control subjects (n = 20). RESULTS: Interleukin 10 levels were significantly elevated in the cerebrospinal fluid of CJD patients (median, 9.8 pg/mL). The elevation was significant to other dementia (median, 7.9 pg/mL, P<.05), motoneuron disease (median, 7.9 pg/mL, P<.05), normal pressure hydrocephalus (median, 7.0 pg/mL, P<.05), and controls (median, 1.3 pg/mL, P<.001). Levels of interleukin 4 were significantly elevated in cerebrospinal fluid of patients with CJD (median, 26.4 pg/mL) compared with control subjects (median, 6.2 pg/mL, P<.001) and patients with a motoneuron disease (median, 10.5 pg/mL, P<.001) CONCLUSIONS: Elevated levels of the anti-inflammatory cytokines interleukin 4 and interleukin 10 in cerebrospinal fluid of patients with CJD are new findings. The data of the present study provide a clue toward the possible role of cytokines as immunological modifiers in the neurodegenerative process of CJD.

Clinical course in young patients with sporadic Creutzfeldt-Jakob disease.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disease with the greatest incidence occurring in patients between 60 and 70 years old. Younger patients may also be affected. In this study, we used all case material available from 52 patients with sCJD aged 50 years or younger at disease onset, who were identified between 1993 and 2003 in Germany. The objective of this study was to describe the psychiatric and neurological features of these young patients with emphasis on the different codon 129 genotypes and PrP types, and to compare them with elder patients with sCJD and patients with variant CJD. We also gave particular attention to electroencephalogram, magnetic resonance imaging, and 14-3-3 results, as well as to the neuropathological lesion profile. The clinical syndrome in young patients differs from elder patients with CJD with respect to clinical signs, disease duration, technical investigations, and neuropathological lesion profile. The psychiatric symptoms in young patients with sCJD are similar to the psychiatric symptoms expressed by patients with variant CJD; however, in contrast with the variant cases, young patients with sCJD experience development of prominent dementia early in the disease course.

Human prion diseases: molecular and clinical aspects.

Compared with that of other human pathogens, the proposed replicative cycle of prions is disarmingly simple. It encompasses misfolding of a single protein, the cellular prion protein (PrPC), into a disease-associated form called PrPSc. This is followed by PrPSc aggregation and possibly fragmentation of aggregates, which may augment the number of replicative units. Although there is no formal proof of the correctness of this model, a wealth of evidence indicates that pathogen-encoded informational nucleic acids are dispensable for prion replication. Despite the simplicity of the replicative process, the human phenotypic range of prion diseases is extremely variable and includes the sporadic, inherited, and acquired forms of Creutzfeldt-Jakob disease. In addition, prion diseases occur in a wide range of animals and can be propagated within and between animal species. The present review article discusses current concepts and controversies surrounding the basic biological features of prions.