Detection of prions in matching post-mortem skin and cerebrospinal fluid samples using second-generation real-time quaking-induced conversion assay.

Real-time quaking-induced conversion assay (RT-QuIC) exploits templating activity of pathogenic prion protein for ultrasensitive detection of prions. We have utilized second generation RT-QuIC assay to analyze matching post-mortem cerebrospinal fluid and skin samples of 38 prion disease patients and of 30 deceased neurological controls. The analysis of cerebrospinal fluid samples led to 100% sensitivity and 100% specificity, but some samples had to be diluted before the analysis to alleviate the effect of present RT-QuIC inhibitors. The analysis of the corresponding skin samples provided 89.5% sensitivity and 100% specificity. The median seeding dose present in the skin was one order of magnitude higher than in the cerebrospinal fluid, despite the overall fluorescent signal of the skin samples was comparatively lower. Our data support the use of post-mortem cerebrospinal fluid for confirmation of prion disease diagnosis and encourage further studies of the potential of skin biopsy samples for intra-vitam prion diseases´ diagnostics.

Levels of plasma brain-derived tau and p-tau181 in Alzheimer's disease and rapidly progressive dementias.

INTRODUCTION: Rapidly progressive dementias (RPDs) are a group of neurological disorders characterized by a rapid cognitive decline. The diagnostic value of blood-based biomarkers for Alzheimer's disease (AD) in RPD has not been fully explored. METHODS: We measured plasma brain-derived tau (BD-tau) and p-tau181 in 11 controls, 15 AD patients, and 33 with RPD, of which 19 were Creutzfeldt-Jakob disease (CJD). RESULTS: Plasma BD-tau differentiated AD from RPD and controls (p = 0.002 and p = 0.03, respectively), while plasma and cerebrospinal fluid (CSF) p-tau181 distinguished AD from RPD (p < 0.001) but not controls from RPD (p > 0.05). The correlation of CSF t-tau with plasma BD-tau was stronger (r = 0.78, p < 0.001) than the correlation of CSF and plasma p-tau181 (r = 0.26, p = 0.04). The ratio BD-tau/p-tau181 performed equivalently to the CSF t-tau/p-tau181 ratio, differentiating AD from CJD (p < 0.0001). DISCUSSION: Plasma BD-tau and p-tau181 mimic their corresponding cerebrospinal fluid (CSF) markers. P-tau significantly increased in AD but not in RPD. Plasma BD-tau, like CSF t-tau, increases according to neurodegeneration intensity.

Systematic approach to diagnosing suspected Creutzfeldt-Jakob disease.

Evaluation of rapidly progressive dementia (RPD) is usually challenging. In most cases, patients progress to dementia in weeks to months, and the differential diagnosis is broad. In this case, a woman in her 60s presented with a 1-month history of episodic vertigo, cognitive decline, ataxia and myoclonus. Cerebrospinal fluid total tau was markedly elevated, which was helpful in establishing the diagnosis and discussing prognosis/end-of-life measures with the patient's family. This case summarises a stepwise diagnostic approach for patients with RPD and highlights recent literature on biomarkers of Creutzfeldt-Jakob disease and autoimmune encephalitis.

High diagnostic performance of plasma and cerebrospinal fluid beta-synuclein for sporadic Creutzfeldt-Jakob disease.

Beta-synuclein is a promising cerebrospinal fluid and blood biomarker of synaptic damage. Here we analysed its accuracy in the discrimination between sporadic Creutzfeldt-Jakob disease (n = 150) and non-prion rapidly progressive dementias (n = 106). In cerebrospinal fluid, beta-synuclein performed better than protein 14-3-3 (AUC 0.95 vs. 0.89) and, to a lesser extent, than total tau (AUC 0.92). Further, the diagnostic value of plasma beta-synuclein (AUC 0.91) outperformed that of plasma tau (AUC 0.79) and neurofilament light chain protein (AUC 0.65) and was comparable to that of cerebrospinal fluid biomarkers. Beta-synuclein might represent the first highly accurate blood biomarker for the diagnosis of sporadic Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2022.

Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2022: Nationwide surveillance of Creutzfeldt-Jakob disease (CJD) and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2022. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2022, a total of 599 domestic CSF specimens were referred for diagnostic testing and 79 persons with suspected human prion disease were formally added to the national register. As of 31 December 2022, just under half of the 79 suspect case notifications (36/79) remain classified as 'incomplete'; 15 cases were classified as 'definite' and 23 as 'probable' prion disease; five cases were excluded through neuropathological examination. For 2022, fifty-five percent of all suspected human-prion-disease-related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. The SARS-CoV-2 pandemic did not affect prion disease surveillance outcomes in Australia during 2022.

Real-time quaking-induced conversion assay using a small-scale substrate production workflow for the diagnosis of Creutzfeldt-Jakob disease.

The lack of a dedicated surveillance program for prion disease, particularly in low- and middle-income countries (LMICs), has hindered the global effort to address this public health threat. Although cerebrospinal fluid (CSF) Real-time quaking-induced conversion (RT-QuIC) is considered the most reliable test for sporadic Creutzfeldt-Jakob disease (sCJD), its availability in LMICs is limited because of its cost and technical difficulty in generating the recombinant prion protein substrate (recPrP). This study aimed to evaluate the performance of RT-QuIC with recPrP produced in-house through a small-scale method-that is, the application of reusable prepacked chromatography columns and subsequent dialysis. Here, CSF specimens from patients suspected of having prion disease were consecutively collected and stored between October 2015 and January 2023. Electronic medical record data were reviewed to clinically classify participants as probable sCJD or non-sCJD. CSF RT-QuIC was performed using in-house recPrP. Its specificity and sensitivity for diagnosing probable sCJD were reported, along with details of other clinical data and investigations. We found that among 39 eligible participants, with a median (interquartile range) age of 64 (56-70) years and 16 (41%) female, 13 had probable sCJD and the remaining 26 unequivocally suffered from nonprion disorders. Magnetic resonance imaging and electroencephalogram were suggestive of sCJD in 100% (13/13) and 46.2% (6/13) of sCJD participants, respectively. RT-QuIC was positive in 12/13 sCJD participants (sensitivity 0.92, 95% confidence interval [CI] 0.67-0.99) and negative in all non-sCJD participants (specificity 1.00, 95% CI 0.87-1.00). CSF tau/p-tau ratio showed sensitivity and specificity of 0.62-1.0 and 0.85-1.0, respectively. In summary, RT-QuIC using recPrP generated through a small-scale workflow demonstrated great performance in detecting sCJD. Given its performance results along with its low cost, this technique could feasibly be implemented in LMICs and potentially be the first step toward establishing local prion disease surveillance programs.

Clinical Correlates of Cerebrospinal Fluid 14-3-3 Protein in Non-Prion Rapid Progressive Dementia.

BACKGROUND: The 14-3-3 protein in cerebrospinal fluid (CSF) is a suitable biomarker for the diagnosis of Creutzfeldt-Jakob disease (CJD). However, it has also been detected in various non-prion-related rapidly progressive dementia (RPD), which affected its diagnostic performance and clinical utilization. OBJECTIVE: To investigate the general disease distribution with positive 14-3-3 result and to evaluate the association between CSF 14-3-3 protein and the clinical features in patients with non-prion RPD. METHODS: A total of 150 patients with non-prion RPD were enrolled. The clinical data were collected and CSF 14-3-3 test was performed for all patients. The distribution of various diseases with a positive 14-3-3 result was analyzed and the association of CSF 14-3-3 with clinical features was tested. RESULTS: The CSF 14-3-3 protein was detected in 23.3% of non-prion RPD patients, and the most frequent diagnoses were autoimmune encephalitis (22.9%) and neurodegenerative disease (22.9%). CSF 14-3-3 protein was more common in older patients (p = 0.028) and those presenting myoclonus (p = 0.008). In subgroup analysis, the positive 14-3-3 test was more common in neurodegenerative disease with a long time from the symptom onset to CSF 14-3-3 test (p = 0.014). CONCLUSION: CSF 14-3-3 protein could be detected in a broad spectrum of non-prion RPD. In particular, patients with autoimmune encephalitis and rapidly progressive neurodegenerative diseases and those with myoclonus have a greater likelihood of a positive 14-3-3 result. These results could help clinicians interpret the results of CSF 14-3-3 protein more reasonably.

Evaluation of the impact of CSF prion RT-QuIC and amended criteria on the clinical diagnosis of Creutzfeldt-Jakob disease: a 10-year study in Italy.

BACKGROUND: The introduction of the prion Real-Time Quaking-Induced Conversion assay (RT-QuIC) has led to a revision of the diagnostic criteria for sporadic Creutzfeldt-Jakob disease (sCJD).Validation studies are needed for the amended criteria, especially for their diagnostic value in the clinical setting. METHODS: We studied 1250 patients with suspected CJD referred for diagnosis to two Italian reference centres between 2010 and 2020. Focusing on the first diagnostic assessment, we compared the diagnostic value of the old and the amended criteria and that of different combinations of clinical variables and biomarker results. RESULTS: The studied cohort comprised 850 participants with CJD (297 definite sCJD, 151 genetic CJD, 402 probable sCJD) and 400 with non-CJD (61 with neuropathology). At first clinical evaluation, the sensitivity of the old criteria (76.8%) was significantly lower than that of the amended criteria (97.8%) in the definite CJD cohort with no difference between definite and probable sCJD cases. Specificity was ~94% for both criteria against the non-CJD cohort (82.0% against definite non-CJD group). Cerebrospinal fluid (CSF) RT-QuIC was highly sensitive (93.9%) and fully specific against definite non-CJD patients. Limiting the criteria to a positive RT-QuIC or/and the combination of a clinical course compatible with possible CJD with a positive MRI (Q-CM criteria) provided higher diagnostic accuracy than both the old and amended criteria, overcoming the suboptimal specificity of ancillary test results (ie, CSF protein 14-3-3). CONCLUSIONS: CSF RT-QuIC is highly sensitive and specific for diagnosing CJD in vitam. The Q-CM criteria provide a high diagnostic value for CJD.

Physiological Consequences of Targeting 14-3-3 and Its Interacting Partners in Neurodegenerative Diseases.

The mammalian 14-3-3 family comprises seven intrinsically unstructured, evolutionarily conserved proteins that bind >200 protein targets, thereby modulating cell-signaling pathways. The presence of 14-3-3 proteins in cerebrospinal fluid provides a sensitive and specific biomarker of neuronal damage associated with Alzheimer's disease (AD), Creutzfeldt−Jakob disease (CJD), spongiform encephalitis, brain cancers, and stroke. We observed significant enrichment of 14-3-3 paralogs G, S, and Z in human brain aggregates diagnostic of AD. We used intra-aggregate crosslinking to identify 14-3-3 interaction partners, all of which were significantly enriched in AD brain aggregates relative to controls. We screened FDA-approved drugs in silico for structures that could target the 14-3-3G/hexokinase interface, an interaction specific to aggregates and AD. C. elegans possesses only two 14-3-3 orthologs, which bind diverse proteins including DAF-16 (a FOXO transcription factor) and SIR-2.1 (a sensor of nutrients and stress), influencing lifespan. Top drug candidates were tested in C. elegans models of neurodegeneration-associated aggregation and in a human neuroblastoma cell-culture model of AD-like amyloidosis. Several drugs opposed aggregation in all models assessed and rescued behavioral deficits in C. elegans AD-like neuropathy models, suggesting that 14-3-3 proteins are instrumental in aggregate accrual and supporting the advancement of drugs targeting 14-3-3 protein complexes with their partners.

Diagnostic Utility of Cerebrospinal Fluid α-Synuclein in Creutzfeldt-Jakob Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) can be difficult to distinguish clinically from some non-prion neurological diseases. Previous studies have reported markedly increased levels of α-synuclein in cerebrospinal fluid (CSF) of CJD patients, indicating that it is a potential diagnostic biomarker. OBJECTIVE: The aim of this study was to assess the diagnostic power of CSF α-synuclein in discriminating CJD from non-prion disorders. METHODS: The Ovid MEDLINE, Cochrane, and Embase databases were searched for articles published on or before February 25, 2022, using the search term (prion diseases OR Creutzfeldt-Jakob syndrome) AND (synuclein OR α-synuclein). The difference in CSF α-synuclein levels between CJD and non-prion diseases was calculated using random-effects models (I2 > 50%) or fixed-effects models (I2 < 50%) in terms of standardized mean difference (SMD) and 95% confidence interval (CI). The publication bias was estimated using funnel plots and the Egger's test. RESULTS: Ten studies were included in this study. The concentrations of CSF α-synuclein were significantly higher in CJD patients compared to total non-prion controls (SMD = 1.98, 95% CI 1.60 to 2.36, p < 0.00001), tauopathies (SMD = 1.34, 95% CI 0.99 to 1.68, p < 0.00001), synucleinopathies (SMD = 1.78, 95% CI 1.11 to 2.44, p < 0.00001), or Alzheimer's (SMD = 1.14, 95% CI 0.95 to 1.33, p < 0.00001). CSF α-synuclein could distinguish CJD from non-prion diseases with overall sensitivity of 89% (95% CI 80-95%), specificity of 92% (95% CI 86-95%), and AUC of 0.96 (95% CI: 0.94-0.97). CONCLUSION: CSF α-synuclein has excellent diagnostic value in discriminating CJD from non-prion neurological diseases. Given the high heterogeneity among the included studies, further studies are needed to confirm its clinical utility.

Alzheimer's disease cerebrospinal fluid biomarkers differentiate patients with Creutzfeldt-Jakob disease and autoimmune encephalitis.

BACKGROUND AND PURPOSE: Autoimmune encephalitis (AE) is a potentially treatable cause of rapidly progressive dementia that may mimic Creutzfeldt-Jakob disease (CJD). Alzheimer disease (AD) cerebrospinal fluid (CSF) biomarkers may discriminate CJD from AD, but utility in discriminating CJD and AE is unclear. This study compared AD CSF biomarkers in CJD and AE. METHODS: Patients with probable or definite CJD and probable or definite AE who underwent Roche Elecsys AD CSF biomarker testing at Mayo Clinic from March 2020 through April 2021 were included. Total-tau, phosphorylated181 tau and amyloid-ß42 levels were compared. RESULTS: Of 11 CJD cases, four were autopsy proven; the rest had positive real-time quaking-induced conversion testing. Disease-associated autoantibodies were detected in 8/15 cases of AE: leucine-rich glioma-inactivated 1 and neuronal intermediate filaments (two cases each), and N-methyl-d-aspartate receptor, contactin-associated protein-like 2, dipeptidyl-peptidase-like protein 6 and immunoglobulin-like cell adhesion molecule IgLON family member 5. Total-tau provided excellent discrimination between CJD and AE in a univariate model (odds ratio 1.46 per 100 pg/ml, 95% confidence interval 1.17-2.11, p < 0.05, c = 0.93). Total-tau was elevated in 91% of CJD cases (median > 1300, range 236->1300 pg/ml), of which 55% were above the limit of assay measurement (>1300 pg/ml). Total-tau was elevated in 20% of AE cases (median 158, range 80->1300 pg/ml). CONCLUSION: Total-tau was greater in CJD than AE. Given that amyloid-ß42 and phosphorylated181 tau were comparable, the ratio differences were probably driven by elevated total-tau in CJD. This study supports the role for AD biomarker testing in patients with rapidly progressive dementia.

Concordance of cerebrospinal fluid real-time quaking-induced conversion across the European Creutzfeldt-Jakob Disease Surveillance Network.

BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) has a high degree of sensitivity and specificity for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) and this has led to its being included in revised European CJD Surveillance Network diagnostic criteria for sCJD. As CSF RT-QuIC becomes more widely established, it is crucial that the analytical performance of individual laboratories is consistent. The aim of this ring-trial was to ascertain the degree of concordance between European countries undertaking CSF RT-QuIC. METHODS: Ten identical CSF samples, seven from probable or neuropathologically confirmed sCJD and three from non-CJD cases, were sent to 13 laboratories from 11 countries for RT-QuIC analysis. A range of instrumentation and different recombinant prion protein substrates were used. Each laboratory analysed the CSF samples blinded to the diagnosis and reported the results as positive or negative. RESULTS: All 13 laboratories correctly identified five of the seven sCJD cases and the remaining two sCJD cases were identified by 92% of laboratories. Of the two sCJD cases that were not identified by all laboratories, one had a disease duration >26 months with a negative 14-3-3, whilst the remaining case had a 4-month disease duration and a positive 14-3-3. A single false positive CSF RT-QuIC result was observed in this study. CONCLUSIONS: This study shows that CSF RT-QuIC demonstrates an excellent concordance between centres, even when using a variety of instrumentation, recombinant prion protein substrates and CSF volumes. The adoption of CSF RT-QuIC by all CJD surveillance centres is recommended.

Role of Biomarkers for the Diagnosis of Prion Diseases: A Narrative Review.

Prion diseases are progressive and irreversible neurodegenerative disorders with a low incidence (1.5-2 cases per million per year). Genetic (10-15%), acquired (anecdotal) and sporadic (85%) forms of the disease have been described. The clinical spectrum of prion diseases is very varied, although the most common symptoms are rapidly progressive dementia, cerebellar ataxia and myoclonus. Mean life expectancy from the onset of symptoms is 6 months. There are currently diagnostic criteria based on clinical phenotype, as well as neuroimaging biomarkers (magnetic resonance imaging), neurophysiological tests (electroencephalogram and polysomnogram), and cerebrospinal fluid biomarkers (14-3-3 protein and real-time quaking-induced conversion (RT-QuIC)). The sensitivity and specificity of some of these tests (electroencephalogram and 14-3-3 protein) is under debate and the applicability of other tests, such as RT-QuIC, is not universal. However, the usefulness of these biomarkers beyond the most frequent prion disease, sporadic Creutzfeldt-Jakob disease, remains unclear. Therefore, research is being carried out on new, more efficient cerebrospinal fluid biomarkers (total tau, ratio total tau/phosphorylated tau and neurofilament light chain) and potential blood biomarkers (neurofilament light chain, among others) to try to universalize access to early diagnosis in the case of prion diseases.

Cerebrospinal fluid neurofilament light chain differentiates primary psychiatric disorders from rapidly progressive, Alzheimer's disease and frontotemporal disorders in clinical settings.

INTRODUCTION: Many patients with cognitive and neuropsychiatric symptoms face diagnostic delay and misdiagnosis. We investigated whether cerebrospinal fluid (CSF) neurofilament light (NfL) and total-tau (t-tau) could assist in the clinical scenario of differentiating neurodegenerative (ND) from psychiatric disorders (PSY), and rapidly progressive disorders. METHODS: Biomarkers were examined in patients from specialist services (ND and PSY) and a national Creutzfeldt-Jakob registry (Creutzfeldt-Jakob disease [CJD] and rapidly progressive dementias/atypically rapid variants of common ND, RapidND). RESULTS: A total of 498 participants were included: 197 ND, 67 PSY, 161 CJD, 48 RapidND, and 20 controls. NfL was elevated in ND compared to PSY and controls, with highest levels in CJD and RapidND. NfL distinguished ND from PSY with 95%/78% positive/negative predictive value, 92%/87% sensitivity/specificity, 91% accuracy. NfL outperformed t-tau in most real-life clinical diagnostic dilemma scenarios, except distinguishing CJD from RapidND. DISCUSSION: We demonstrated strong generalizable evidence for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy.

Total and Phosphorylated Cerebrospinal Fluid Tau in the Differential Diagnosis of Sporadic Creutzfeldt-Jakob Disease and Rapidly Progressive Alzheimer's Disease.

BACKGROUND: CSF total-tau (t-tau) became a standard cerebrospinal fluid biomarker in Alzheimer's disease (AD). In parallel, extremely elevated levels were observed in Creutzfeldt-Jakob disease (CJD). Therefore, tau is also considered as an alternative CJD biomarker, potentially complicating the interpretation of results. We investigated CSF t-tau and the t-tau/phosphorylated tau181 ratio in the differential diagnosis of sCJD and rapidly-progressive AD (rpAD). In addition, high t-tau concentrations and associated tau-ratios were explored in an unselected laboratory cohort. METHODS: Retrospective analyses included n = 310 patients with CJD (n = 205), non-rpAD (n = 65), and rpAD (n = 40). The diagnostic accuracies of biomarkers were calculated and compared. Differential diagnoses were evaluated in patients from a neurochemistry laboratory with CSF t-tau >1250 pg/mL (n = 199 out of 7036). RESULTS: CSF t-tau showed an AUC of 0.942 in the discrimination of sCJD from AD and 0.918 in the discrimination from rpAD. The tau ratio showed significantly higher AUCs (p < 0.001) of 0.992 versus non-rpAD and 0.990 versus rpAD. In the neurochemistry cohort, prion diseases accounted for only 25% of very high CSF t-tau values. High tau-ratios were observed in CJD, but also in non-neurodegenerative diseases. CONCLUSIONS: CSF t-tau is a reliable biomarker for sCJD, but false positive results may occur, especially in rpAD and acute encephalopathies. The t-tau/p-tau ratio may improve the diagnostic accuracy in centers where specific biomarkers are not available.

Prodynorphin and Proenkephalin in Cerebrospinal Fluid of Sporadic Creutzfeldt-Jakob Disease.

Proenkephalin (PENK) and prodynorphin (PDYN) are endogenous opioid peptides mainly produced in the striatum and, to a lesser extent, in the cerebral cortex. Dysregulated metabolism and altered cerebrospinal fluid (CSF) levels of PENK and PDYN have been described in several neurodegenerative diseases. However, no study to date investigated these peptides in the CSF of sporadic Creutzfeldt-Jakob disease (sCJD). Using liquid chromatography-multiple reaction monitoring mass spectrometry, we evaluated the CSF PDYN- and PENK-derived peptide levels in 25 controls and 63 patients with sCJD belonging to the most prevalent molecular subtypes (MM(V)1, VV2 and MV2K). One of the PENK-derived peptides was significantly decreased in each sCJD subtype compared to the controls without a difference among subtypes. Conversely, PDYN-derived peptides were selectively decreased in the CSF of sCJD MV2K, a subtype with a more widespread overall pathology compared to the sCJD MM(V)1 and the VV2 subtypes, which we confirmed by semiquantitative analysis of cortical and striatal neuronal loss and astrocytosis. In sCJD CSF PENK and PDYN were associated with CSF biomarkers of neurodegeneration but not with clinical variables and showed a poor diagnostic performance. CSF PDYN and PENK-derived peptides had no significant diagnostic and prognostic values in sCJD; however, the distinct marker levels between molecular subtypes might help to better understand the basis of phenotypic heterogeneity determined by divergent neuronal targeting.

Diagnostic accuracy of cerebrospinal fluid biomarkers for the differential diagnosis of sporadic Creutzfeldt-Jakob disease: a (network) meta-analysis.

BACKGROUND: There are no systematic reviews of cerebrospinal fluid and blood biomarkers for sporadic Creutzfeldt-Jakob disease (sCJD) in specialized care settings that compare diagnostic accuracies in a network meta-analysis (NMA). METHODS: We searched Medline, Embase, and Cochrane Library for diagnostic studies of sCJD biomarkers. Studies had to use established diagnostic criteria for sCJD and for diseases in the non-CJD groups, which had to represent a consecutive population of patients suspected as a CJD case, as reference standard. Risk of bias was assessed with QUADAS-2. We conducted individual biomarker meta-analyses with generalized bivariate models. To investigate heterogeneity, we performed subgroup analyses based on QUADAS-2 quality and clinical criteria. For the NMA, we applied a Bayesian beta-binomial ANOVA model. The study protocol was registered at PROSPERO (CRD42019118830). RESULTS: Of 2976 publications screened, we included 16 studies, which investigated 14-3-3ß (n = 13), 14-3-3γ (n = 3), neurofilament light chain (NfL, n = 1), neuron-specific enolase (n = 1), p-tau181/t-tau ratio (n = 2), RT-QuIC (n = 7), S100B (n = 3), t-tau (n = 12), and t-tau/Aß42 ratio (n = 1). Excluded diagnostic studies had strong limitations in study design. In the NMA, RT-QuIC (0.91; 95% CI [0.83, 0.95]) and NfL (0.93 [0.78, 0.99]) were the most sensitive biomarkers for the diagnosis of definite, probable, and possible sCJD cases. RT-QuIC was the most specific biomarker (0.97 [0.89, 1.00]). Heterogeneity in accuracy estimates was high between studies. CONCLUSIONS: We identified RT-QuIC as the most accurate biomarker, partially confirming currently applied diagnostic criteria. The shortcomings identified in many diagnostic studies for sCJD biomarkers need to be addressed in future studies.

Comparison of cerebrospinal fluid tau, ptau(181), synuclein, and 14-3-3 for the detection of Creutzfeldt-Jakob disease in clinical practice.

Creutzfeldt-Jakob disease (CJD) is the leading human prion disease and is a major public health concern, with the risk of secondary iatrogenic transmission. Screening for CJD is often based on the detection of 14-3-3 protein in cerebrospinal fluid (CSF) through western blot assay and, in a second step, on a more specific method such as RT-QuIC (Real-Time Quaking-Induced Conversion). Alternatives to the detection of 14-3-3 in CSF have recently been proposed, specifically CSF tau proteins, tau/p-tau(181) ratio, and alpha-synuclein. In the present work, we compare the diagnostic performance of these biomarkers with that of 14-3-3 protein in a cohort of suspected CJD patients. Our results indicate that tau detection is the most effective and suitable approach for routine disease detection in a clinical setting. Combination with other biomarkers does not improve overall performance, while the tau/p-tau(181) ratio remains useful for differentiating Alzheimer's from CJD. In the end, the performance of tau protein detection in CSF reached 78% sensitivity and 80% specificity for the detection of CJD. It is interesting to note that the use of an automated method with a high concentration range allows for rapid and accurate results, which is very useful in clinical practice and allows for confirmatory testing such as RT-QuIC without delay.

Experience with Creutzfeldt-Jakob disease in a single referral center in Mexico. Case series.

INTRODUCTION: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and fatal central nervous system disease caused by prions. OBJECTIVE: To present the main clinical and paraclinical characteristics of patients with probable CJD in a referral center of Latin America. METHODS: Retrospective study of patients diagnosed with rapidly progressive dementia between 2014 and 2019. Clinical, demographic, electroencephalogram, magnetic resonance imaging, and 14-3-3 protein characteristics were included, as well as positron-emission tomography (PET) data when available. RESULTS: Twenty-four patients met the criteria for sporadic CJD (75% were women). Mean age was 59.29 ± 11.67 years, while mean disease duration from symptom onset to hospital admission was 7.41 ± 6.54 months. The most common first symptom was behavioral changes (41.7%). Delta wave complexes prevailed (54.2%) on electroencephalogram, cortical hyperintensity (83.3%) on magnetic resonance and frontal hypometabolism (37.5%) on PET. Seven cases showed positive total Tau; five, positive 14-3-3 protein; and three, positive phosphorylated tau on cerebrospinal fluid analysis. CONCLUSIONS: There is significant clinical heterogeneity regarding initial symptoms. Auxiliary test findings were consistent with those of other series.

INTRODUCCIÓN: La enfermedad de Creutzfeldt-Jakob (ECJ) es una enfermedad del sistema nervioso central rápidamente progresiva y mortal causada por priones. OBJETIVO: Presentar las principales características clínicas y paraclínicas de pacientes con probable ECJ en un centro de referencia de América Latina. MÉTODOS: Estudio retrospectivo de pacientes diagnosticados con demencia rápidamente progresiva entre 2014 y 2019. Se incluyeron características clínicas, demográficas, del electroencefalograma, imágenes por resonancia magnética, proteína 14-3-3 y tomografía por emisión de positrones (PET), cuando estaba disponible. RESULTADOS: Veinticuatro pacientes cumplieron con los criterios de ECJ esporádica (75 % mujeres), la edad media fue de 59.29 ± 11.67 años, la duración de la enfermedad desde el inicio de los síntomas hasta el ingreso hospitalario fue de 7.41 ± 6.54 meses y las primeras manifestaciones más comunes fueron las alteraciones del comportamiento (41.7 %). Los complejos de ondas delta prevalecieron en el electroencefalograma (54.2 %), la hiperintensidad cortical en la resonancia magnética (83.3 %) y el hipometabolismo frontal en la PET (37.5 %). En el análisis del líquido cefalorraquídeo, siete casos mostraron proteína tau total positiva; cinco, proteína 14-3-3 positiva; y tres, proteína tau hiperfosforilada positiva. CONCLUSIONES: Existe importante heterogeneidad clínica en cuanto a los síntomas iniciales. Los hallazgos de las pruebas auxiliares coincidieron con los de otras series.

NT1-Tau Is Increased in CSF and Plasma of CJD Patients, and Correlates with Disease Progression.

This study investigates the diagnostic and prognostic potential of different forms of tau in biofluids from patients with Creutzfeldt-Jakob disease (CJD). Extracellular tau, which is molecularly heterogeneous, was measured using ultra-sensitive custom-made Simoa assays for N-terminal (NT1), mid-region, and full-length tau. We assessed cross-sectional CSF and plasma from healthy controls, patients with Alzheimer's disease (AD) and CJD patients. Then, we evaluated the correlation of the best-performing tau assay (NT1-tau) with clinical severity and functional decline (using the MRC Prion Disease Rating Scale) in a longitudinal CJD cohort (n = 145). In a cross-sectional study, tau measured in CSF with the NT1 and mid-region Simoa assays, separated CJD (n = 15) from AD (n = 18) and controls (n = 21) with a diagnostic accuracy (AUCs: 0.98-1.00) comparable to or better than neurofilament light chain (NfL; AUCs: 0.96-0.99). In plasma, NT1-measured tau was elevated in CJD (n = 5) versus AD (n = 15) and controls (n = 15). Moreover, in CJD plasma (n = 145) NT1-tau levels correlated with stage and rate of disease progression, and the effect on clinical progression was modified by the PRNP codon 129. Our findings suggest that plasma NT1-tau shows promise as a minimally invasive diagnostic and prognostic biomarker of CJD, and should be further investigated for its potential to monitor disease progression and response to therapies.