Novel diagnostic and prognostic approach for rapidly progressive dementias: Indicators based on amyloid/tau/neurodegeneration (ATN) framework.

AIMS: Apply established cerebrospinal fluid (CSF) and serum biomarkers and novel combined indicators based on the amyloid/tau/neurodegeneration (ATN) framework to improve diagnostic and prognostic power in patients with rapidly progressive dementias (RPDs). METHODS: CSF and serum biomarkers of Alzheimer's disease (AD) common neuropathology including Aß42, Aß40, p-Tau, and t-Tau were measured in cognitively normal (CN) controls (n = 33) and three RPD groups with rapidly progressive AD (rpAD, n = 23), autoimmune encephalitis (AE, n = 25), and Creutzfeldt-Jakob disease (CJD, n = 28). Logistic regression and multiple linear regression were used for producing combined indicators and prognostic assessment, respectively, including A&T, A&N, T&N, A&T&N, etc. RESULTS: Combined diagnostic indicator with A&T&N had the potential for differentiating AE from other types of RPDs, identifying 62.51% and 75% of AE subjects based on CSF and serum samples, respectively, compared to 39.13% and 37.5% when using autoantibodies. CSF t-Tau was associated with survival in the CJD group (adjusted R-Square = 0.16, p = 0.02), and its prognosis value improved when using combined predictors based on the ATN framework (adjusted R-Square = 0.273, p = 0.014). CONCLUSION: Combined indicators based on the ATN framework provide a novel perspective for establishing biomarkers for early recognition of RPDs due to treatment-responsive causes.

Diagnostic and Prognostic Value of Plasma GFAP in Sporadic Creutzfeldt-Jakob Disease in the Clinical Setting of Rapidly Progressive Dementia.

The diagnostic and prognostic value of plasma glial fibrillary acidic protein (pl-GFAP) in sporadic Creutzfeldt-Jakob disease (sCJD) has never been assessed in the clinical setting of rapidly progressive dementia (RPD). Using commercially available immunoassays, we assayed the plasma levels of GFAP, tau (pl-tau), and neurofilament light chain (pl-NfL) and the CSF total tau (t-tau), 14-3-3, NfL, phospho-tau181 (p-tau), and amyloid-beta isoforms 42 (Aß42) and 40 (Aß40) in sCJD (n = 132) and non-prion RPD (np-RPD) (n = 94) patients, and healthy controls (HC) (n = 54). We also measured the CSF GFAP in 67 sCJD patients. Pl-GFAP was significantly elevated in the sCJD compared to the np-RPD and HC groups and affected by the sCJD subtype. Its diagnostic accuracy (area under the curve (AUC) 0.760) in discriminating sCJD from np-RPD was higher than the plasma and CSF NfL (AUCs of 0.596 and 0.663) but inferior to the 14-3-3, t-tau, and pl-tau (AUCs of 0.875, 0.918, and 0.805). Pl-GFAP showed no association with sCJD survival after adjusting for known prognostic factors. Additionally, pl-GFAP levels were associated with 14-3-3, pl-tau, and pl-NfL but not with CSF GFAP, Aß42/Aß40, and p-tau. The diagnostic and prognostic value of pl-GFAP is inferior to established neurodegeneration biomarkers. Nonetheless, pl-GFAP noninvasively detects neuroinflammation and neurodegeneration in sCJD, warranting potential applications in disease monitoring.

Has the frequency of ABO RhD blood groups in Australian blood donors changed as a result of the removal of the variant Creutzfeldt-Jakob disease-based deferral?

BACKGROUND AND OBJECTIVES: Until 25 July 2022, Australians who had spent more than 6 months in the United Kingdom or territories between 1980 and 1996 were deferred from blood donation due to the risk of variant Creutzfeldt-Jakob disease. Removal of this geography-based donor deferral on RhD-negative blood availability has not been reported. MATERIALS AND METHODS: All donors who donated at least once from 25 July 2022 to 25 July 2023 were included. UK donor status, first-time donor and ABO RhD data were extracted from the National Blood Management System. RESULTS: Data from 566,447 blood donors with a valid ABO RhD result were analysed. Of these, 34,560 were new or returning lapsed donors following removal of the UK donor deferral. The median age [range] in years for all donors was 43 [75] with UK donors being older 53 [70]. There was a higher prevalence of RhD-negative status in UK donors (20.2%) compared with first-time blood donors (15.7%). CONCLUSION: UK donors were generally older, female and more likely to be RhD-negative. Although UK donors provided a boost to RhD-negative blood collections, the overall prevalence of ABO RhD blood groups in the total Australian blood donor panel remained similar to previous estimates.

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.

Distribution of microRNA profiles in pre-clinical and clinical forms of murine and human prion disease.

Prion diseases are distinguished by long pre-clinical incubation periods during which prions actively propagate in the brain and cause neurodegeneration. In the pre-clinical stage, we hypothesize that upon prion infection, transcriptional changes occur that can lead to early neurodegeneration. A longitudinal analysis of miRNAs in pre-clinical and clinical forms of murine prion disease demonstrated dynamic expression changes during disease progression in the affected thalamus region and serum. Serum samples at each timepoint were collected whereby extracellular vesicles (EVs) were isolated and used to identify blood-based biomarkers reflective of pathology in the brain. Differentially expressed EV miRNAs were validated in human clinical samples from patients with human sporadic Creutzfeldt-Jakob disease (sCJD), with the molecular subtype at codon 129 either methionine-methionine (MM, n = 14) or valine-valine (VV, n = 12) compared to controls (n = 20). EV miRNA biomarkers associated with prion infection predicted sCJD with an AUC of 0.800 (85% sensitivity and 66.7% specificity) in a second independent validation cohort (n = 26) of sCJD and control patients with MM or VV subtype. This study discovered clinically relevant miRNAs that benefit diagnostic development to detect prion-related diseases and therapeutic development to inhibit prion infectivity.

Plasma and cerebrospinal fluid ABeta42 for the differential diagnosis of Alzheimer's disease dementia in participants diagnosed with any dementia subtype in a specialist care setting.

BACKGROUND: Dementia is a syndrome that comprises many differing pathologies, including Alzheimer's disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta-amyloid (1-42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes. OBJECTIVES: To determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome. SEARCH METHODS: We searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies. SELECTION CRITERIA: We considered cross-sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype. DATA COLLECTION AND ANALYSIS: Seven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the 'Quality Assessment of Diagnostic Accuracy Studies' (QUADAS-2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross-tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta-analyses using bivariate, random-effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs). In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non-ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol-related cognitive disorder (ARCD), Creutzfeldt-Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test-positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42. MAIN RESULTS: We identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS-2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies). The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non-ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity. AUTHORS' CONCLUSIONS: Our review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non-ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis.

Comparison between plasma and cerebrospinal fluid biomarkers for the early diagnosis and association with survival in prion disease.

OBJECTIVE: To compare the diagnostic accuracy and the prognostic value of blood and cerebrospinal fluid (CSF) tests across prion disease subtypes. METHODS: We used a single-molecule immunoassay to measure tau and neurofilament light chain (NfL) protein levels in the plasma and assessed CSF total(t)-tau, NfL and protein 14-3-3 levels in patients with prion disease (n=336), non-prion rapidly progressive dementias (n=106) and non-neurodegenerative controls (n=37). We then evaluated each plasma and CSF marker for diagnosis and their association with survival, taking into account the disease subtype, which is a strong independent prognostic factor in prion disease. RESULTS: Plasma tau and NfL concentrations were higher in patients with prion disease than in non-neurodegenerative controls and non-prion rapidly progressive dementias. Plasma tau showed higher diagnostic value than plasma NfL, but a lower accuracy than the CSF proteins t-tau and 14-3-3. In the whole prion cohort, both plasma (tau and NfL) and CSF (t-tau, 14-3-3 and NfL) markers were significantly associated with survival and showed similar prognostic values. However, the intrasubtype analysis revealed that only CSF t-tau in sporadic Creutzfeldt-Jakob disease (sCJD) MM(V)1, plasma tau and CSF t-tau in sCJD VV2, and plasma NfL in slowly progressive prion diseases were significantly associated with survival after accounting for covariates. CONCLUSIONS: Plasma markers have lower diagnostic accuracy than CSF biomarkers. Plasma tau and NfL and CSF t-tau are significantly associated with survival in prion disease in a subtype-specific manner and can be used to improve clinical trial stratification and clinical care.

A blood miRNA signature associates with sporadic Creutzfeldt-Jakob disease diagnosis.

Sporadic Creutzfeldt-Jakob disease (sCJD) presents as a rapidly progressive dementia which is usually fatal within six months. No clinical blood tests are available for diagnosis or disease monitoring. Here, we profile blood microRNA (miRNA) expression in sCJD. Sequencing of 57 sCJD patients, and healthy controls reveals differential expression of hsa-let-7i-5p, hsa-miR-16-5p, hsa-miR-93-5p and hsa-miR-106b-3p. Downregulation of hsa-let-7i-5p, hsa-miR-16-5p and hsa-miR-93-5p replicates in an independent cohort using quantitative PCR, with concomitant upregulation of four mRNA targets. Absence of correlation in cross-sectional analysis with clinical phenotypes parallels the lack of association between rate of decline in miRNA expression, and rate of disease progression in a longitudinal cohort of samples from 21 patients. Finally, the miRNA signature shows a high level of accuracy in discriminating sCJD from Alzheimer's disease. These findings highlight molecular alterations in the periphery in sCJD which provide information about differential diagnosis and improve mechanistic understanding of human prion diseases.

Preclinical Detection of Prions in Blood of Nonhuman Primates Infected with Variant Creutzfeldt-Jakob Disease.

Variant Creutzfeldt-Jakob disease (vCJD) is caused by prion infection with bovine spongiform encephalopathy and can be transmitted by blood transfusion. Protein misfolding cyclic amplification (PMCA) can detect prions in blood from vCJD patients with 100% sensitivity and specificity. To determine whether PMCA enables prion detection in blood during the preclinical stage of infection, we performed a blind study using blood samples longitudinally collected from 28 control macaques and 3 macaques peripherally infected with vCJD. Our results demonstrate that PMCA consistently detected prions in blood during the entire preclinical stage in all infected macaques, without false positives from noninfected animals, when using the optimized conditions for amplification of macaque prions. Strikingly, prions were detected as early as 2 months postinoculation (>750 days before disease onset). These findings suggest that PMCA has the potential to detect vCJD prions in blood from asymptomatic carriers during the preclinical phase of the disease.

Plasma YKL-40 in the spectrum of neurodegenerative dementia.

BACKGROUND: Increased plasma YKL-40 has been reported in Alzheimer's disease (AD), but its levels in other neurodegenerative diseases are unknown. Here, we aimed to investigate plasma YKL-40 in the spectrum of neurodegenerative dementias. METHODS: YKL-40 was quantified in the plasma of 315 cases, including healthy controls (HC), neurological disease controls (ND), AD, vascular dementia (VaD), frontotemporal dementia (FTD), sporadic Creutzfeldt-Jakob disease (CJD) and Lewy body dementia (LBD). Diagnostic accuracy in the differential diagnostic context and influence of age and gender was assessed. RESULTS: Highest YKL-40 levels were detected in CJD, followed by LBD, VaD, AD, FTD, ND and HC. YKL-40 was associated to age but not to sex. After controlling for age, YKL-40 was significantly elevated in CJD compared to HC (p < 0.001), ND, AD and VaD (p < 0.01) and in LBD compared to HC (p < 0.05). In CJD, YKL-40 concentrations were significantly higher at late disease stages. CONCLUSIONS: Plasma YKL-40 is significantly elevated in CJD regardless of clinical and genetic parameters, with moderate diagnostic accuracy in the discrimination from control cases. Our study discards a potential use of this biomarker in the differential diagnostic context but opens the possibility to be explored as a marker for CJD monitoring.

Learning from history: Lord Brain and Hashimoto's encephalopathy.

We present two historic cases of severe encephalopathy associated with antithyroid antibodies. The first was published by Lord Brain of Eynsham, and the second was from our department's archives. Although both cases are from archival sources, they continue to inform current clinical care. We briefly review the poorly defined entity, Hashimoto's encephalopathy, and discuss diagnostic advances for autoimmune encephalopathy and for Creutzfeldt-Jakob disease. We advocate for giving a trial of corticosteroids to patients with 'encephalopathy, not otherwise specified' while awaiting antibody results or more definitive testing. Our case, initially diagnosed as having Creutzfeldt-Jakob disease, responded remarkably (with video evidence) to a trial of corticosteroids.

Sporadic Creutzfeldt-Jakob disease presenting as dizziness and cognitive decline: A case report.

RATIONALE: Creutzfeldt-Jakob disease (CJD) is an infrequent and rapidly fatal neurodegenerative disease without effective cure. Common presentations of CJD include rapidly progressive cognitive decline, behavioral changes, cerebellar dysfunction, and visual disturbances. Since clinicians may see only very few cases during their professional career, it is important to be familiar with the clinical presentation and progression, and allow for quick diagnosis. PATIENT CONCERNS: We reported an elderly woman had recurrent attacks of dizziness in the preceding month. She began to suffer progression of memory disturbance half a month before admission and was admitted to our department in a coma. DIAGNOSIS: The accessory examinations of magnetic resonance imaging (MRI), electroencephalography (EEG), 14-3-3 protein in cerebrospinal fluid and S100 protein in serum support the diagnosis of sporadic CJD (sCJD). Combined with this evidence and clinical symptom, we made a clinical diagnosis of sCJD. INTERVENTIONS: Supportive treatment. OUTCOMES: After 2 months of active treatment, the patient's condition had not improved, and the patient died 82 days after admission. LESSONS: Clinicians should attach importance to sCJD, which is significant for the prevention of transmission and treatment.

Review: Fluid biomarkers in the human prion diseases.

The human prion diseases are a diverse set of often rapidly progressive neurodegenerative conditions associated with abnormal forms of the prion protein. We review work to establish diagnostic biomarkers and assays that might fill other important roles, particularly those that could assist the planning and interpretation of clinical trials. The field now benefits from highly sensitive and specific diagnostic biomarkers using cerebrospinal fluid: detecting by-products of rapid neurodegeneration or specific functional properties of abnormal prion protein, with the second generation real time quaking induced conversion (RT-QuIC) assay being particularly promising. Blood has been a more challenging analyte, but has now also yielded valuable biomarkers. Blood-based assays have been developed with the potential to screen for variant Creutzfeldt-Jakob disease, although it remains uncertain whether these will ever be used in practice. The very rapid neurodegeneration of prion disease results in strong signals from surrogate protein markers in the blood that reflect neuronal, axonal, synaptic or glial pathology in the brain: notably the tau and neurofilament light chain proteins. We discuss early evidence that such tests, applied alongside robust diagnostic biomarkers, may have potential to add value as clinical trial outcome measures, predictors of future disease course (including for asymptomatic individuals at high risk of prion disease), and as rapidly accessible and sensitive markers to aid early diagnosis.

Neurofilament light chain and tau concentrations are markedly increased in the serum of patients with sporadic Creutzfeldt-Jakob disease, and tau correlates with rate of disease progression.

OBJECTIVES: A blood-based biomarker of neuronal damage in sporadic Creutzfeldt-Jakob disease (sCJD) will be extremely valuable for both clinical practice and research aiming to develop effective therapies. METHODS: We used an ultrasensitive immunoassay to measure two candidate biomarkers, tau and neurofilament light (NfL), in serum from patients with sCJD and healthy controls. We tested longitudinal sample sets from six patients to investigate changes over time, and examined correlations with rate of disease progression and associations with known phenotype modifiers. RESULTS: Serum concentrations of both tau and NfL were increased in patients with sCJD. NfL distinguished patients from controls with 100% sensitivity and 100% specificity. Tau did so with 91% sensitivity and 83% specificity. Both tau and NfL appeared to increase over time in individual patients, particularly in those with several samples tested late in their disease. Tau, but not NfL, was positively correlated with rate of disease progression, and was particularly increased in patients homozygous for methionine at codon 129 of PRNP. CONCLUSIONS: These findings independently replicate other recent studies using similar methods and offer novel insights. They show clear promise for these blood-based biomarkers in prion disease. Future work should aim to fully establish their potential roles for monitoring disease progression and response to therapies.

Creutzfeldt-Jakob disease and blood transfusion safety.

Transmissible spongiform encephalopathies (TSEs) are untreatable, fatal neurologic diseases affecting mammals. Human disease forms include sporadic, familial and acquired Creutzfeldt-Jakob disease (CJD). While sporadic CJD (sCJD) has been recognized for near on 100 years, variant CJD (vCJD) was first reported in 1996 and is the result of food-borne transmission of the prion of bovine spongiform encephalopathy (BSE, 'mad cow disease'). Currently, 230 vCJD cases have been reported in 12 countries, the majority in the UK (178) and France (27). Animal studies demonstrated highly efficient transmission of natural scrapie and experimental BSE by blood transfusion and fuelled concern that sCJD was potentially transfusion transmissible. No such case has been recorded and case-control evaluations and lookback studies indicate that, if transfusion transmission occurs at all, it is very rare. In contrast, four cases of apparent transfusion transmission of vCJD infectivity have been identified in the UK. Risk minimization strategies in response to the threat of vCJD include leucodepletion, geographically based donor deferrals and deferral of transfusion recipients. A sensitive and specific, high-throughput screening test would provide a potential path to mitigation but despite substantial effort no such test has yet appeared. The initial outbreak of vCJD appears to be over, but concern remains about subsequent waves of disease among those already infected. There is considerable uncertainty about the size of the infected population, and there will be at least a perception of some continuing risk to blood safety. Accordingly, at least some precautionary measures will remain in place and continued surveillance is necessary.

The associations of two SNPs in miRNA-146a and one SNP in ZBTB38-RASA2 with the disease susceptibility and the clinical features of the Chinese patients of sCJD and FFI.

Prion diseases are a group of fatal neurodegenerative disorders that affect humans and animals. Besides of the pathological agent, prion, there are some elements that can influence or determine susceptibility to prion infection and the clinical phenotype of the diseases, e.g., the polymorphism in PRNP gene. Another polymorphism in ZBTB38-RASA2 has been observed to be associated with the susceptibility of sporadic Creutzfeldt-Jacob disease (sCJD) in UK. MicroRNAs are endogenous small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. In this study, two polymorphic loci in miR-146a (rs2910164 and rs57095329) and one locus in ZBTB38-RASA2 (rs295301) of 561 Chinese patients of sCJD and 31 cases of fatal familial insomnia (FFI) were screened by PCR and sequencing. Our data did not figure out any association of those three SNPs with the susceptibility of sCJD. However, a significant association of the SNP of rs57095329 in miR-146a showed the association with the susceptibility of FFI. Additionally, the SNP of rs57095329 showed statistical significances with the appearances of mutism and the positive of cerebrospinal fluid (CSF) protein 14-3-3 in sCJD patients, while the SNP of ZBTB38-RASA2 was significantly related with the appearance of myoclonus in sCJD patients. It indicates that the SNPs of ZBTB38-RASA2 and miR-146a are not associated with the susceptibility of the Chinese sCJD patients, but may influence the appearances of clinical manifestations somehow.

Clinical findings of a probable case of MM2-cortical-type sporadic Creutzfeldt-Jakob disease with antibodies to anti-N-terminus of α-enolase.

We report the case of a 76-year-old woman presenting with 47-month history of progressive dementia and cortical blindness with no family history. Antibodies against thyroid glands and the N-terminus of α-enolase (NAE) were detected in her serum. Neurological examination revealed progressive dementia, frontal signs, visual disturbance, and exaggerated bilateral tendon reflexes in both legs. Diffusion MRI showed cortical hyper-intensities in the bilateral occipital and parietal, and the left frontal and temporal cortices. 99mTc-ethyl cysteinate dimer-single photon emission computed tomography indicated decreased regional cerebral blood flow throughout the bilateral parietal lobes and partially in the left frontal and temporal lobes. PRNP gene analysis showed no mutations with methionine homozygosity at codon 129 in peripheral blood. Cerebrospinal fluid examination, including 14-3-3 and total tau protein detection, revealed normal levels; however, prion proteins were amplified by the real-time quaking-induced conversion method. Hashimoto's encephalopathy was excluded on the basis of unresponsiveness to corticosteroids. The symptoms progressed slowly. Periodic sharp-wave complexes were observed on electroencephalogram 36 months after the onset of symptoms; the patient reached a state of akinetic mutism at 47 months. This was a probable case of MM2-cortical-type sCJD with anti-NAE antibodies based on the World Health Organization (WHO) diagnostic criteria for sCJD, genetic information, and the slowly progressive course. However, this case did not meet with the probable WHO diagnostic criteria until 3 years after symptom onset, highlighting the difficulty of diagnosing a living case of the MM2-type of sCJD. Therefore, establishment of clinical diagnostic criteria for MM2-type of sCJD is required.

Geographic exposure risk of variant Creutzfeldt-Jakob disease in US blood donors: a risk-ranking model to evaluate alternative donor-deferral policies.

BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) has been transmitted by blood transfusion (TTvCJD). The US Food and Drug Administration (FDA) recommends deferring blood donors who resided in or traveled to 30 European countries where they may have been exposed to bovine spongiform encephalopathy (BSE) through beef consumption. Those recommendations warrant re-evaluation, because new cases of BSE and vCJD have markedly abated. STUDY DESIGN AND METHODS: The FDA developed a risk-ranking model to calculate the geographic vCJD risk using country-specific case rates and person-years of exposure of US blood donors. We used the reported country vCJD case rates, when available, or imputed vCJD case rates from reported BSE and UK beef exports during the risk period. We estimated the risk reduction and donor loss should the deferral be restricted to a few high-risk countries. We also estimated additional risk reduction by leukocyte reduction (LR) of red blood cells (RBCs). RESULTS: The United Kingdom, Ireland, and France had the greatest vCJD risk, contributing approximately 95% of the total risk. The model estimated that deferring US donors who spent extended periods of time in these three countries, combined with currently voluntary LR (95% of RBC units), would reduce the vCJD risk by 89.3%, a reduction similar to that achieved under the current policy (89.8%). Limiting deferrals to exposure in these three countries would potentially allow donations from an additional 100,000 donors who are currently deferred. CONCLUSION: Our analysis suggests that a deferral option focusing on the three highest risk countries would achieve a level of blood safety similar to that achieved by the current policy.

Detection of prions in the plasma of presymptomatic and symptomatic patients with variant Creutzfeldt-Jakob disease.

Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease resulting from the consumption of meat products contaminated by the agent causing bovine spongiform encephalopathy. Evidence supporting the presence of a population of silent carriers that can potentially transmit the disease through blood transfusion is increasing. The development of a blood-screening assay for both symptomatic vCJD patients and asymptomatic carriers is urgently required. We show that a diagnostic assay combining plasminogen-bead capture and protein misfolding cyclic amplification (PMCA) technologies consistently detected minute amounts of abnormal prion protein from French and British vCJD cases in the required femtomolar range. This assay allowed the blinded identification of 18 patients with clinical vCJD among 256 plasma samples from the two most affected countries, with 100% sensitivity [95% confidence interval (CI), 81.5 to 100%], 99.2% analytical specificity (95% CI, 95.9 to 100%), and 100% diagnostic specificity (95% CI, 96.5 to 100%). This assay also allowed the detection of silent carriage of prions 1.3 and 2.6 years before the clinical onset in two blood donors who later developed vCJD. These data provide a key step toward the validation of this PMCA technology as a blood-based diagnostic test for vCJD and support its potential for detecting presymptomatic patients, a prerequisite for limiting the risk of vCJD transmission through blood transfusion.