The Bayesian approach for real-world implementation of plasma p-tau217 in tertiary care memory clinics in Thailand.

INTRODUCTION: Plasma phosphorylated tau (p-tau)217 is a promising biomarker for Alzheimer's disease (AD) diagnosis, but its clinical implementation remains challenging. We propose a strategy based on Bayes' theorem and test it in real-life memory clinics. METHODS: Memory clinic patients were evaluated by neurocognitive specialists for prespecified diagnosis and subsequently underwent blood collection for p-tau217, cerebrospinal fluid, or amyloid positron emission tomography. Using cross-validation, the Bayesian approach (pretest probability × individualized likelihood ratio) was compared to other models for AD diagnosis. RESULTS: The Bayesian strategy demonstrated an area under the receiver operating characteristic curve (AUC) of 0.98 (95% confidence interval [CI]: 0.96-1.0), significantly outperforming multivariable logistic regression (p-tau217, age, apolipoprotein E; AUC 0.95, p = 0.024) and p-tau217 alone (AUC = 0.94, p = 0.007). When applying the two-threshold approach, the Bayesian strategy yielded an accuracy of 0.94 (95% CI: 0.88-1.0) without requiring confirmatory tests in 62.9% of the iterations. DISCUSSION: The Bayesian strategy offers an effective and flexible approach to address the limitations of plasma p-tau217 in clinical practice. HIGHLIGHTS: Incorporating pretest probability into the interpretation of plasma phosphorylated tau (p-tau)217 improves the diagnostic performance significantly. The strategy could obviate the need for confirmatory testing in most of the patients. Plasma p-tau217 proves useful as a biomarker for Alzheimer's disease in low- and middle-income country such as Thailand.

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.

Prospective evaluation of plasma phosphorylated tau in a real-life memory clinic in Thailand.

INTRODUCTION: Despite the substantial accuracy of plasma p-tau in diagnosing Alzheimer's disease (AD) in research cohorts, data on real-life memory clinic patients are lacking. METHODS: Memory clinic patients at their early symptomatic stages were prospectively enrolled to undergo routine clinical assessment, plasma p-tau181 quantification (Simoa), amyloid and tau-positron emission tomography (PET). The diagnostic performance of plasma p-tau181, neurocognitive specialists, and regional tau-PET were compared head-to-head using amyloid-PET as the reference standard. RESULTS: Plasma p-tau181 has the area under the curve (AUC), sensitivity, specificity, and accuracy of 0.84 (95% confidence interval [CI] 0.73-0.94), 0.80 (95% CI 0.64-0.90), 0.75 (95% CI 0.51-0.90), and 0.78 (95% CI 0.65-0.88) for detecting amyloid-PET positivity in early symptomatic patients, respectively. The AUC of clinical diagnosis and tau-PET were 0.70 (95% CI 0.56-0.85) and 0.88 (95% CI 0.79-0.97), respectively. DISCUSSION: Plasma p-tau181 also performed well in real-life memory clinic settings and its role in clinical practice is supported.

COVID-19 related acute necrotizing encephalopathy with extremely high interleukin-6 and RANBP2 mutation in a patient with recently immunized inactivated virus vaccine and no pulmonary involvement.

BACKGROUND: We report the first case of COVID-19 associated acute necrotizing encephalopathy (ANE) without pulmonary disease in a patient with an extremely high interleukin-6 (IL-6) level and Ran Binding Protein 2 (RANBP2) mutation. CASE PRESENTATION: A 29-year-old woman recently immunized with inactivated viral vaccine-BBIBP32-CorV (Sinopharm) presented with alteration of consciousness. Her body temperature was 37° Celsius, blood pressure 42/31 mmHg, heart rate 130 bpm, respiratory rate 20 per minute, and oxygen saturation 98%. Respiratory examination was unremarkable. Neurological examination revealed stupor but preserved brainstem reflexes. Non-contrast computerized tomography of the brain showed symmetrical hypodense lesions involving bilateral thalami and cerebellar hemispheres characteristic of ANE. No pulmonary infiltration was found on chest radiograph. SARS-CoV-2 was detected by PCR; whole genome sequencing later confirmed the Delta variant. RANBP2 gene analysis revealed heterozygous Thr585Met mutation. Serum IL-6 was 7390 pg/mL. Urine examination showed pyelonephritis. Her clinical course was complicated by seizure, septic shock, acute kidney injury, and acute hepatic failure. She later developed coma and passed away in 6 days. CONCLUSIONS: ANE is caused by cytokine storm leading to necrosis and hemorrhage of the brain. IL-6 was deemed as a prognostic factor and a potential treatment target of ANE in previous studies. RANBP2 missense mutation strongly predisposes this condition by affecting mitochondrial function, viral entry, cytokine signaling, immune response, and blood-brain barrier maintenance. Also, inactivated vaccine has been reported to precipitate massive production of cytokines by antibody dependent enhancement (ADE). The true incidence of COVID-19 associated ANE is not known as were the predictors of its development. We proposed these potential two factors (RANBP2 mutation and ADE) that could participate in the pathogenesis of ANE in COVID-19 apart from SARS-CoV2 infection by itself. Further study is needed to confirm this hypothesis, specifically in the post-vaccination period. Role of RANBP2 mutation and its application in COVID-19 and ANE should be further elaborated.

Neurofilament light is associated with clinical outcome and hemorrhagic transformation in moderate to severe ischemic stroke.

Background: Ischemic stroke is a leading cause of morbidity and mortality worldwide. One possible predictor is the use of biomarkers especially neurofilament light chain (NFL). Objectives: To explore whether NFL could predict clinical outcome and hemorrhagic transformation in moderate to severe stroke. Design: Single center prospective cohort study. Methods: Fifty-one moderate to severe ischemic stroke patients were recruited. Blood NFL was obtained from patients at admission (First sample) and 24-96 hours later (Second sample). NFL was analyzed with the ultrasensitive single molecule array (Simoa). Later, we calculated incremental rate NFL (IRN) by changes in NFL per day from baseline. We evaluated National Institute of Health stroke scale (NIHSS), modified Rankins score (mRs), and the presence of hemorrhagic transformation (HT). Results: IRN was found to be higher in patients with unfavorable outcome (7.12 vs 24.07, P = .04) as well as Second sample (49.06 vs 71.41, P = .011), while NFL First sample was not significant. IRN had a great correlation with mRS (r = .552, P < .001). Univariate logistic regression model showed OR of IRN and Second sample to be 1.081 (95% CI 1.016-1.149, P = .013) and 1.019 (1.002-1.037, P = .03), respectively. Multiple logistic regression model has shown to be significant. In receiver operating analysis, IRN, Second sample, combined IRN with NIHSS and combined Second sample with NIHSS showed AUC (.744, P = .004; 0.713, P = .01; 0.805, P < .001; 0.803, P < .001, respectively). For HT, First sample and Second sample had significant difference with HT (Z = 2.13, P = .033; Z = 2.487, P = .013, respectively). Conclusion: NFL was found to correlate and predict clinical outcome. In addition, it was found to correlate with HT.

Neurofilament light chain for classifying the aetiology of alteration of consciousness.

Neurofilament light chain has become a promising biomarker for neuroaxonal injury; however, its diagnostic utility is limited to chronic disorders or specific contexts. Alteration of consciousness is a common clinical problem with diverse aetiologies, many of which require timely diagnoses. We evaluated the value of neurofilament light chain alone, as well as creating diagnostic models, in distinguishing causes of alteration of consciousness. Patients presenting with alteration of consciousness were enrolled. Initial clinical data of each participant were evaluated by a neurologist to give a provisional diagnosis. Each participant subsequently received advanced investigations and follow-up to conclude the final diagnosis. All diagnoses were classified into a structural or non-structural cause of alteration of consciousness. Plasma and cerebrospinal fluid levels of neurofilament light chain were measured. Cerebrospinal fluid neurofilament light chain and other clinical parameters were used to develop logistic regression models. The performance of cerebrospinal fluid neurofilament light chain, the neurologist's provisional diagnosis, and the model to predict the final diagnosis were compared. For the results, among 71 participants enrolled, 67.6% and 32.4% of their final diagnoses were classified as structural and non-structural, respectively. Cerebrospinal fluid neurofilament light chain demonstrated an area under the curve of 0.75 (95% confidence interval 0.63-0.88) which was not significantly different from a neurologist's provisional diagnosis 0.85 (95% confidence interval 0.75-0.94) (P = 0.14). The multivariable regression model using cerebrospinal fluid neurofilament light chain and other basic clinical data achieved an area under the curve of 0.90 (95% confidence interval 0.83-0.98). In conclusion, neurofilament light chain classified causes of alteration of consciousness with moderate accuracy. Nevertheless, including other basic clinical data to construct a model improved the performance to a level that was comparable to clinical neurologists.

Elevation of plasma phosphorylated tau181 during neurological illnesses affecting consciousness and kidney dysfunction.

Introduction: Phosphorylated tau (p-tau)181 has become a promising blood-based Alzheimer's disease (AD) biomarker. We studied the agreement of plasma p-tau181 and cerebrospinal fluid (CSF) markers in patients with alteration of consciousness (AOC). Methods: Plasma and CSF were simultaneously collected in participants presenting with AOC. Plasma p-tau181 was measured using the single-molecule array. CSF biomarkers were classified according to the amyloid/tau/neurodegeneration (AT[N]) framework. Results: Among participants enrolled, the median (interquartile range) age was 57 (28.5-75) years and 5.8% had AD. Plasma p-tau181 yielded area under the curve of 0.85 and showed moderate correlation with CSF p-tau181 (Rho = 0.42, P < .001). Using the historical cut-point, many non-AD participants had elevated plasma p-tau181 resulting in a specificity of 0.57. Plasma p-tau181 correlated with the glomerular filtration rate (Rho = -0.52, P < .001). Among A- participants with elevated plasma p-tau181, 42% had kidney dysfunction. Discussion: Plasma p-tau181 showed inadequate specificity in patients with AOC partially attributable to concomitant kidney dysfunction.