Keywords

1 Introduction

Human prion diseases share many common features—transmissibility in animal experiments, fatal progressive disease course, neuronal loss, astrogliosis, and PrPSc deposition in the brain. Despite this, several forms are distinguished depending on assumed pathophysiology: genetic, acquired, and sporadic disease forms. In addition, sporadic disease forms display clinicopathological diversity, which origins in codon 129 PRNP genotype and PrPSc type (see Molecular disease subtypes). In clinical terms, signs and symptoms of the disease are heterogeneous and comprise a wide spectrum of neurological and psychiatric abnormalities. Because of this and because of the fact that a definite early clinical test or biomarker is still lacking, several diagnostic investigations have to be taken into account and considered in the context of comprehensive clinical examination, thoughtful evaluation of the clinical history, and consideration of other differential, potentially curable diagnoses.

A definite and final diagnosis requires invasive procedures such as brain biopsy or analysis of brain material at autopsy. Early detection will become increasingly important once forthcoming effective therapies are available (Krammer et al. 2009). Clinical diagnostic criteria for sCJD were first suggested 40 years ago, using a combination of distinctive clinical features and best available investigations, which at that time was EEG (Masters et al. 1979). In recent years, substantial progress in developing other specialized investigations, including useful surrogate biomarkers in the cerebrospinal fluid, plasma and brain imaging, and clinical diagnostic criteria, have been amended (Collins et al. 2006; Zerr et al. 2000, 2009, 2022; Hermann et al. 2021) (Fig. 33.1). Blood-based biomarker are currently under investigations and might become important tools for monitoring disease progression and potentially even response to therapy once disease-modifying drugs become available (Vallabh et al. 2020).

Fig. 33.1
The timeline of the development of diagnosis from 1970 to 2020, brain biopsy, E E G, C S F, M R I, R T Q u I C, and blood with elevated levels of tau, N f L, and P r P.

Progress in the development of diagnostic techniques for Creutzfeldt–Jakob disease (CJD). (Zerr 2022)

Full size image

2 Cerebrospinal Fluid

Cerebrospinal fluid (CSF) is the main component of the brain extracellular space and participates in the exchange of many biochemical products in the central nervous system (CNS). Consequently, CSF contains a dynamic and complex mixture of proteins, which reflects physiological or pathological state of the CNS. CSF analysis is an important part in clinical neurology and is used to diagnose various inflammatory and malignant disorders and recently also neurodegenerative disorders. The alterations in CSF composition are also discussed to reflect pathological changes in the brain and thus contribute to a better understanding of the pathophysiology of the underlying disorders affecting CNS.

For many years, CSF analysis in CJD has been used to exclude brain inflammation in patients with rapid progressive dementia. Since modern proteomic technologies allow us to identify proteins and protein patterns in human fluids, the CSF analysis in dementia disorders has become even more important. Historically, first CSF abnormalities in human prion diseases were reported by Harrington et al. (1986), who identified two proteins spots, named p130/131 in the CSF of CJD patients. Decades later, these proteins became known as 14-3-3 proteins and were the first CSF biomarker ever used in clinical criteria in patients with a neurodegenerative dementia.

2.1 Routine Tests

The routine examination of CSF from patients with CJD or GSS usually reveals normal results. An unspecific increase in total protein, the presence of oligoclonal IgG bands or raised cell count is an extremely rare finding (see Table 33.1). In the most comprehensive study on this subject, data from 450 patients with sporadic CJD and 47 patients with other TSEs were analyzed as part of an EC-supported multinational study. Raised white cell counts of >5 cells/ml were found in three out of 298 patients with sporadic CJD, in two with cell counts of 7 cells/ml and in one of 20 cells/ml. Total protein concentrations of >0.9 g/l were found in 5 of 438 patients with sporadic CJD, but none had a concentration of >1 g/l. CSF oligoclonal IgG was detected in 8 out of 182 sporadic CJD patients. Among patients with other TSEs, six had elevated cell counts ranging from 6 to 14 cells/ml, but none had total protein concentrations of >0.9 g/l and one patient had detectable oligoclonal IgG. None of the patients with sporadic CJD or other TSEs had abnormalities in all three tests (Green et al. 2007).

Table 33.1 Frequency of abnormal CSF white cell counts, raised total proteins, and the presence of oligoclonal IgG
Full size table

As a rule, inflammatory CSF findings exclude the diagnosis of a human prion disease.

2.2 14-3-3 Proteins

14-3-3 proteins were initially described as abundant, acidic brain proteins, and their names are derived from the combination of its fraction number on DEAE-cellulose chromatography and migration position in the subsequent starch gel electrophoresis (Hsich et al. 1996). Despite the fact that the pathology behind the elevated level of 14-3-3 in CJD is still a question of debate, the detection of 14-3-3 protein in CSF is part of clinical diagnostic criteria for probable sCJD because of its high sensitivity and, even more important, high predictive values in clinical setting. A large number of studies proved that in appropriate clinical circumstances, a positive 14-3-3 is highly sensitive and specific for sCJD diagnosis. A meta-analysis showed a sensitivity of 92% and a specificity of 80% of Western Blot 14-3-3 analyses (Muayqil et al. 2012). The recently developed γ14-3-3 ELISA was reported with 88% sensitivity and 96% specificity (Schmitz et al. 2016a, b) and showed superior diagnostic accuracy in a comparative evaluation (Leitão et al. 2016). However, the specificity may be substantially lower in the differentiation from acute non-neurodegenerative encephalopathies (Stoeck et al. 2012).

The sensitivity of 14-3-3 varies among TSE types. Whereas very high sensitivity was shown in gCJD and iatrogenic CJD, similar to sCJD, 14-3-3 positivity is substantially less frequent in GSS and rarely present in FFI (Llorens et al. 2020a, b, c; Schmitz et al. 2022). In variant CJD (vCJD), only about 49% of patients are positive (Green et al. 2001; Gmitterová et al. 2009; Green et al. 2002; Van Everbroeck et al. 2003; Castellani et al. 2004).

Biological parameters significantly influence the sensitivity of 14-3-3 test in patients with sCJD, that is, disease duration, codon 129 genotype, age at onset, and time of the lumbar puncture (Sanchez-Juan et al. 2007). In general, the 14-3-3 test displays best sensitivity in patients older than 40 years with short disease duration, homozygous at codon 129 genotype, and when lumbar puncture is performed at later disease stages (Sanchez-Juan et al. 2006). Differences in the sensitivity of 14-3-3 test are also observed between classical and nonclassical CJD types (see Molecular disease subtypes). In classical CJD (which basically fulfills the criteria of having the tendency to be older, homozygous for methionine at codon 129, short disease duration, and rapid progression), 14-3-3 test sensitivity is superior to nonclassical (or atypical) cases.

Although this test was often found to be positive at onset of the first neurological symptoms, higher sensitivity was reported in the middle or late stage of the disease. Moreover, in the terminal stage of disease, 14-3-3 level might decrease in CSF, but this observation is based on case reports and might reflect extremely long disease duration.

2.3 Tau/p-tau

Tau concentration in CSF of CJD patients is highly increased, and its quantitative analysis is a good diagnostic tool for CJD (Kovacs et al. 2017c). Determination of tau has shown to yield specificity and sensitivity comparable to those for 14-3-3 testing, and several studies revealed that the optimum cut-off point for CJD is at 1.300 pg/ml (Hermann et al. 2021). This cut-off is three times higher than levels reported for Alzheimer’s dementia. In the latter, extreme tau levels have been reported occasionally, especially in atypical or rapidly-progressive Alzheimer’s dementia. Therefore, a ratio of phosphorylated and total t-tau has been proposed to improve the diagnostic accuracy (Skillbäck et al. 2014, Hermann et al. 2022) Concerning the phosphorylated tau isoforms in CSF of CJD, tau phosphorylated at threonine 181 (p-tau) was significantly raised in sCJD as well as in vCJD. Interestingly, tau concentration was lower in vCJD when compared to sCJD, whereas p-tau concentration was much higher in vCJD than in sCJD.

2.4 RT-QuIC

The Real-Time Quaking-induced conversion (RT-QuIC) is a new method to detect PrPSc in various tissues and body fluids. The method is described in detail in chapter 30. Since 2011, it has been evaluated in the context of the clinical diagnosis of sCJD in several retrospective and prospective studies. Because all studies reported good to excellent Sensitivity with outstanding specificity of 99%–100% (see a summary in Table 33.2), it was integrated as a new diagnostic criterion in recent consensus criteria. If available, the test should be performed in all patients with suspected prion disease (Hermann et al. 2021).

Table 33.2 Diagnostic accuracy of CSF RT-QuIC in retrospective and prospective studies (Hermann et al. 2021)
Full size table

2.5 Other CSF Markers

Besides common TSE markers, several other proteins have been proposed as possibly useful in the diagnosis of the human TSE. So far, they were tested in small numbers of patients and need further rigorous testing and thoughtful validation of their potentials to be classified as biomarkers in human prion disorders (Table 33.3). Hermann et al. Lancet Neurol 2021.

Table 33.3 Other reported cerebrospinal fluid candidates for markers of human prion diseases
Full size table

2.6 Blood-Based Biomarkers

Blood-based biomarkers to detect disease or to monitor disease progression are highly desirable because they would replace CSF puncture or at least support the diagnostic process. In addition, blood samples can be taken regularly and repeatedly. Attempts to develop blood-based biomarkers have been carried out for many years (Otto et al. 1998; Völkel et al. 2001) and have experienced a renewed upswing in recent years. With the improvement of detection technology, some brain proteins can be detected in plasma with good reproducibility. These primarily include the proteins tau, NFL (Steinacker et al. 2016), and PrP (Villar-Piqué et al. 2019). Elevated levels may correlate with disease stage and progression but, unfortunately, the specificity of tau and NFL in the differential diagnosis from other rapidly progressive encephalopathic syndromes is not very high (Kovacs et al. 2017; Abu-Rumeileh et al. 2020a; Zerr et al. 2021). See Table 33.4 for a summary of recent studies. However, the sensible use may be to monitor the disease progression or as a surrogate marker to check the therapy effects in clinical trials (Thompson et al. 2021).

Table 33.4 Diagnostic performance of serum or plasma markers for sCJD (Hermann et al. 2021)
Full size table

3 Magnetic Resonance Imaging

3.1 General Introduction

MRI has played an important role in the diagnosis of CJD (Tschampa et al. 2005; Urbach et al. 1998; Nozaki et al 2018; Young et al. 2005; Seror et al. 2010). In 1988, a hyperintense signal of the basal ganglia on T2-weighted images was first described as a characteristic finding in sCJD patients, followed by further case reports. Subsequently, systematic studies on the sensitivity and specificity of hyperintense signal changes in the striatum in sCJD were performed. Along with the availability of methods, the early MR studies mainly focused on T2-weighted, proton density weighted (Finkenstaedt et al. 1996; Schröter et al. 2000), and to a lesser extent on FLAIR (Choi et al. 2009) imaging, while current studies and criteria mainly rely on FLAIR and especially DWI MRI (Zerr et al. 2009; Vitali et al. 2011; Bizzi et al. 2020; Lee et al. 2010).

With the emergence of more sensitive MRI techniques, such as fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted image (DWI), cortical signal increase was additionally observed in sCJD patients and hyperintense basal ganglia were detected more frequently (Fig. 33.2). Using FLAIR- and DWI, signal increase in the cortex has been reported even more frequently than basal ganglia signal increase. Apart from the cortex and basal ganglia hyperintensity, signal increase has also been reported for the hippocampus, thalamus, and cerebellum and for the mesencephalon. In general, the most sensitive technique to date seems to be DWI, followed by FLAIR and T2 imaging.

Fig. 33.2
3 images of the axial sections of the diffused weighted image with degenerating cerebral cortex and the space of ventricles are also reduced in the third image.

DWI from patient with CJD representing. (a) Hyperintensities cortical. (b) Symmetric both caudate nucleus plus cortical. (c) striatum right> left plus cortical

Full size image

3.2 Test Performance

With the introduction of diffusion-weighted imaging, MR changes are detected earlier in the disease (Collins et al. 2006; Heinemann et al. 2007b; Josephs et al. 2009) and interobserver reliability was improved (Demaerel et al. 1999, Zerr et al. 2009, Vitali et al. 2011). The diagnostic accuracy was reported by several studies with a sensitivity ranging from 80% to 98% and a specificity ranging from 74% to 98% (Hermann et al. 2021). However, discrepant reports of the test performance may be explained with the use of different criteria, different control groups, and, in particular, may be highly dependent on the image reader’s experience (Carswell et al. 2012).

3.3 Changes During the Disease

Data on serial MR examinations in CJD are limited in the literature. In early disease stages, characteristic basal ganglia lesions are not found in up to one-third of the patients (Meissner et al. 2008). According to Ukisu and colleagues (Ukisu et al. 2005), cortical DWI changes (9/9 cases) preceded the hyperintensities in the basal ganglia (5/9 cases at early stage). During the course of the disease, there is generally an expansion of the signal changes and progressive cerebral atrophy (Tribl et al. 2002; Eisenmenger et al. 2016), displaying lesion propagation from cortex to basal ganglia in MM1 and vice versa in VV2 (Pascuzzo et al. 2020). In the late stage of the disease, the diffusion changes may disappear (Arruda et al. 2004; Tribl et al. 2002). Some very interesting case studies reported very early and even preclinical MRI changes in genetic and sporadic CJD up to two years before disease onset (Alvarez et al. 2005; Zanusso et al. 2016; Novi et al. 2018; Koizumi et al. 2021).

4 EEG

For decades, periodic sharp wave complexes (PSWCs) in the EEG were reported to represent the most typical finding in the course of sCJD. The apparent advantages of the EEG are: This investigation is widely available, noninvasive, and can easily be repeated several times. At onset, the EEG might show only nonspecific changes such as background slowing of alpha activity and dysrhythmia. As the disease progresses, slow periodic complexes might appear occasionally; later, the typical periodic pattern is seen. In end stage of CJD, the EEG might show an isoelectric line. PSWCs might be provoked by acoustic or tactile stimulation. Typical periodic patterns (Fig. 33.3) are observed in 60%–70% of all cases after about 12 weeks (median) from disease onset but might occur as early as three weeks after onset. They may disappear at later disease stages. Since the term PSWCs has not been operationalized before, sensitivity of the detection of this abnormality varied among studies. EEG criteria have been suggested (Fig. 33.4). According to these criteria, PSWCs are detectable in two-thirds of CJD patients at mid and late disease stages (sensitivity 64%) with a specificity of 91% (Steinhoff et al. 2004). However, they are not able to differentiate CJD from nonconvulsive status epilepticus (Marquetand et al. 2017) and in addition, recent observations reported a lower sensitivity (around 40%) (Hermann et al. 2018), most likely due to the fact that modern diagnostics allow the identification of CJD in early disease stages when PSWCs are not present.

Fig. 33.3
A chart with 17 sharp wave complexes acquired by the brain signals.

Typical periodic sharp wave complexes

Full size image
Fig. 33.4
For an image with periodicity, at least 5 complexes, a frequency is 0.5 to 2 per second, and duration of 200 to 600 milliseconds, and an amplitude is more than 150 to 300 microvolts.

EEG criteria (according to Steinhoff et al. 2007)

Full size image

5 Molecular Disease Subtype-Specific Diagnosis

Some years ago, a molecular basis has been defined, which might explain the clinical and pathological disease heterogeneity (Parchi et al. 1996). The polymorphism for methionine (M) or valine (V) at codon 129 of PRNP gene has been shown to influence the clinical features of sCJD. In 1996, two PrPSc subtypes in brain homogenates of sCJD patients were identified. The polymorphism at codon 129 and the prion protein types 1 and 2 were the basis for a new molecular classification of sCJD, which replaced the previous attempts (Parchi et al. 1999). Currently, patients with the MM1/MV1 subtype, who display a short disease duration, dementia, myoclonus, and typical EEG pattern, are frequently referred to as having “classical” or “common” CJD subtype. Other (“nonclassical” and “atypical”) subtypes are rare (Fig. 33.5).

Fig. 33.5
A table on Creutzfeldt Jakob disease subtypes is a molecular subtype, clinical signs, neuropathological findings, and P r P immunohistochemistry which are frequent, rare, or V C J D.

Molecular CJD subtypes

Full size image

The discovery of several distinct molecular CJD subtypes explains many features observed in sporadic CJD patients. The clinical presentation at early disease stage is peculiar in most disease subtypes, and the detailed investigation of the clinical syndrome often allows the assignment to the distinct CJD subtype. This observation is supported by EEG, CSF, and MRI results, which appear in subtype-distinctive pattern as described below. Table 33.5 gives an overview of the diagnostic investigations in distinct molecular CJD subtypes (Heinemann et al. 2007a).

Table 33.5 Different values of the technical investigations EEG, CSF and MRI stratified by CJD subtype
Full size table

EEG is abnormal in all disease subtypes, but the typical periodic sharp and slow wave pattern (PSWC) is observed in MM1/MV1 subtype only and is rare in MM2/ MV2/VV1-2 patients. Because CJD diagnosis was based on the triad: dementia, myoclonus, and PSWC in EEG for a long time, we might speculate that the frequency of so-called classical myoclonic CJD type was overestimated in earlier studies due to the selection bias. As mentioned above, results of various CSF tests vary considerably by disease subtype. 14-3-3 test sensitivity is best in MM1 and VV patients (>90%) and has the lowest sensitivity in MV2 (65%) and MM2 (78%) patients. Similar results were obtained for CSF tau protein (Sanchez-Juan et al. 2006) and for the detection of PrPSc via RT-QuIC (Franceschini et al. 2017; Rhoads et al. 2020).

The most characteristic MRI lesion patterns are found in MV2 and VV2, showing predominant involvement of thalamus and basal ganglia. Limited cortical signal increase was significantly related to PrPSc type 2. A further possible characteristic lesion pattern was found in VV1 showing widespread cortical hyperintensities and absence of basal ganglia signal alterations. In the other subtypes, there was a higher overlap between cortical and subcortical involvement. MV2 subtype was characterized by basal ganglia and thalamic involvement (Krasnianski et al. 2006). The pulvinar sign, according to current criteria, was identified in the MV2 subtype only (Collie et al. 2003). Due to the generally high frequency of thalamic hyperintensities in MV2, this subtype is the most likely to be mistaken for variant CJD (vCJD) on MRI. A multicenter international study evaluated MRI scans in 211 CJD patients with various sCJD disease subtypes (Meissner et al. 2009). Although basal ganglia hyperintensities on the MRI represented a consistent finding in all subtypes (except VV1), the frequency and location of cortex hyperintensities as well as the presence or absence of thalamus involvement varied between the subtypes. Across all molecular subtypes, VV2 patients showed the most frequent involvement of basal ganglia and thalamus. Cerebral cortical signal increase was usually restricted to less than three regions and most frequently found in the cingulate gyrus (Table 33.6 and Fig. 33.6). Recent studies validated these findings and reported that in the most common MM1 subtype, DWI abnormalities are predominantly present in cortical regions and caudate nucleus. VV2 and MV2 subtypes show primary involvement of the striatum and the thalamus, whereas in the rare MM2 and VV1 subtypes, often only cortical abnormalities can be detected (Pascuzzo et al. 2020). Based on these results, Bizzi et al. (2021) proposed an MRI-based prion subtype classification algorithm.

Table 33.6 MRI findings and subtypes
Full size table
Fig. 33.6
6 axial M R I sections of the brain have an obscure appearance of the ventricles with P r P s 1 and 2 and the images taken in M M, M V, and V V.

Characteristic MRI findings in sporadic CJD subtypes

Full size image

6 Genetic TSE

Patients with inherited forms of human prion diseases are diagnosed by genetic analysis of the PRNP gene. However, the family history of a prion disease might be absent in a considerable number of patients, thus it is important to know the outcomes of conventional tests such as EEG, CSF, and MRI. The most comprehensive studies have been carried out in genetic CJD with E200K and V210I mutations and in fatal familial insomnia (FFI), whereas only case reports or very small cohorts have been investigated in rare PRNP mutations.

Genetic transmissible spongiform encephalopathies (gTSE) represent 10%–15% of human TSEs. However, there is a special interest in studying biochemical and imaging markers in CSF to improve diagnosis and to monitor disease progression in genetic forms, especially when disease phenotype differs from that of typical sporadic CJD (Ladogana et al. 2009).

PSWCs are not recorded in Gerstmann–Sträussler–Scheinker (GSS) syndrome, fatal familial insomnia, and in transmitted forms of the disease such as Kuru, iCJD, and vCJD. In patients with genetic prion diseases, PSWCs are only occasionally seen, with exception of patients with the mutation at codon 200 and 210 (Ladogana et al. 2005). In these patients, the sensitivity of the EEG is almost the same as in sCJD (Zerr et al. 1998a).

Concerning CSF 14-3-3 testing, sensitivity varies across the spectrum of genetic mutations (Rosenmann et al. 1997). Apparently, the types of mutation significantly influence the biomarker concentration in the CSF and, thus, test sensitivity. According to current information from a large multicenter study, changes in the CSF of patients with familial genetic forms of CJD (gCJD) are comparable to those found in sCJD samples. Table 33.7 gives an overview. For example, 14-3-3 proteins are detectable in patients with an E200K and V210I mutation but only in rare cases in FFI and GSS (Schmitz et al. 2022). In an another study on biomarkers in CJD (Ladogana et al. 2009), the crude analyses of disease-modifying factors on 14-3-3 test in gCJD revealed that age at onset and PRNP codon 129 genotype influenced sensitivity. Age at onset correlated significantly with 14-3-3 test sensitivity in gCJD, being lower in those patients with disease onset before 40 years. These data parallel the results of the same analysis performed on sporadic CJD (Ladogana et al. 2009; Sanchez-Juan et al. 2006). Interestingly, the PRNP codon 129 genotype seemed to influence 14-3-3 sensitivity in gCJD in a different way as in sporadic CJD. Valine homozygous gCJD patients had a statistically significant lower sensitivity in 14-3-3 test than heterozygous patients, but sensitivity was not significantly lower when adjusted for the mutation. This might be due to the fact that the PRNP mutations coupled with valine alleles (P105T, R208H, D178N, and E196K) yielded lower sensitivity to 14-3-3 (Table 33.8).

Table 33.7 Sensitivity of CSF markers in genetic TSE with most common PRNP mutations
Full size table
Table 33.8 Differential diagnoses of RPD reported by tertiary referral centers (Zerr and Hermann 2018)
Full size table

In recent years, more and more data have become available concerning MRI changes in gCJD. Of special importance, thalamostriatal and cortical diffusion reductions have been shown to precede disease onset in E200K and other prion mutation carriers and might therefore serve as an early diagnostic marker (Lee et al. 2009; Cohen et al. 2015; Koizumi et al. 2021; Fulbright et al 2006; Fulbright et al. 2008; Tsuboi et al. 2005). Restricted diffusion seems to be observed less frequently in gTSE, especially in FFI GSS, than in sCJD (Krasnianski et al. 2016). A Japanese study that included 216 gTSE patients and reported an overall sensitivity of 79% (Nozaki et al. 2010). However, CJD-typical signal patterns are quite common in gTSE associated with typical gCJD mutations such as E200K (Gao et al. 2019).

An important point of interest for biomarkers in gTSEs is to analyze their potential use as surrogate parameter for disease progression in clinical trials. These data might be used for selection of homogenous patient groups when testing new drugs to obtain a more reliable assessment of their effects on the disease progression and to reduce the sample size needed in clinical trials. In addition, such biomarkers might be used to monitor the disease progression (Vallabh et al. 2020, Hermann et al. 2020, Thompson et al. 2021).

7 Differential Diagnosis

The differential diagnosis of sCJD includes a large number of neurological and psychiatric diseases (Van Everbroeck et al. 2004; Schmidt et al. 2010; Maat et al. 2015; Chitravas et al. 2011; Papageorgiu et al. 2009). In most cases, the diagnosis of CJD as the primary diagnosis is not taken into account when patients are admitted to hospital. Alzheimer’s disease is the most important differential diagnosis in older patients. Rapid disease courses, in particular, can rarely be discriminated from CJD, especially when myoclonus is present. Dementia with Lewy bodies is another neurodegenerative dementia that must be considered (Gaig et al. 2011). Because CJD typically presents as a rapidly evolving neurological disorder, the spectrum of differential diagnosis also comprises some treatable or reversible diseases or acute conditions. Figure 33.7 gives an overview on differential diagnoses of CJD in specialized centers. It indicates that potentially reversible conditions may be present in about 30% of suspected prion disease cases (Kelley et al. 2008). Moreover, studies from nonspecialized centers reported that immune-mediated and infectious encephalitides were the most frequent diagnosis among patients with rapidly progressive dementia (Zhang et al. 2017; Studart Neto et al. 2017; Anuja et al. 2018). Thus, a clinical suspicion of prion disease has to be validated through biomarker-based diagnostics and a thorough exclusion of potential mimics before a final diagnosis is made.

Fig. 33.7
A bar graph on the number of cases of progressive dementia seen in different countries. The highest number of cases of A D is seen in Cleveland, U S A.

Diagnosis of rapid progressive dementia in % in various retrospective analyses of surveillance/neurology units

Full size image

8 Criteria

The symptoms and signs of disease in patients with prion diseases are heterogeneous. This heterogeneity is the result of the involvement of various brain structures and still undefined biological determinants influencing disease course. The classification criteria are based on the etiology of the disease, which can be divided into four categories: sporadic, iatrogenic, familial/genetic, and variant CJD (WHO 2003; Will et al. 2000; Zerr et al. 2009; Hermann et al. 2021). Criteria for sporadic CJD have been amended by 14-3-3 CSF test, MRI, and more recently, detection of the PrPSc. They are displayed in Fig. 33.8.

Fig. 33.8
A chart on the diagnosis of sporadic Creutzfeldt Jakob disease with definite, probable, and possible categories.

Criteria for sporadic CJD. http://cjd-goettingen.de/en/for-doctors/criteria-of-sporadic-cjd

Full size image

9 Conclusions

Creutzfeldt–Jakob disease is a frequent cause of rapid progressive dementia. Achieving a correct early diagnosis has important implications for (1) distinguishing prion disease from other, potentially treatable diseases, (2) preventing infectious material from being distributed via blood transfusions, surgery, or organ donations, and (3) selecting homogeneous population for upcoming drug trials. The clinical diagnosis of sCJD is supported by detection of biomarkers in blood or CSF, including the biomarkers such as 14-3-3 and tau/phosphorylated tau and recently detection of the abnormal PrP in the CSF. Clinical diagnostic criteria were amended and validated (Hermann et al. 2021, Watson et al. 2022). Advanced brain imaging techniques significantly contribute to the clinical diagnosis, on the one hand, but might also help in the early differentiation of molecular disease subtypes in sporadic CJD, on the other hand.

Progress in development of blood-based biomarker is substantial and will further add to the development of monitoring strategies once powerful anti-prion drugs will appear on the horizon.