Diagnostic performance of cerebrospinal fluid biomarkers in Creutzfeldt-Jakob disease Results from the Swedish mortality registry

Abstract

Master thesis, Programme in Medicine. TITLE: Diagnostic performance of cerebrospinal fluid biomarkers in Creutzfeldt-Jakob disease Results from the Swedish mortality registry. AUTHOR: Tobias Skillbäck. Background: Distinguishing the invariably lethal prion disease Creutzfeldt-Jakob disease (CJD) from non-prion rapidly progressive dementias is important and sometimes difficult, and reliable tools for diagnosis are thus in great demand. Cerebrospinal fluid (CSF) levels of total tau (T-tau) and phosphorylated tau (P-tau) have been used to identify patients with CJD in small studies. Here, we wanted to validate the diagnostic performance of CSF T-tau, P-tau and the T-tau/P-tau-ratio by analyzing results from a large database of clinical routine samples, in combination with diagnosis information from the Swedish mortality registry. Methods: We cross-referenced the Swedish mortality registry with a dataset of CSF measurements of T-tau and P-tau performed in clinical routine at the Clinical Neurochemistry Laboratory of the Sahlgrenska University Hospital, serving most of Sweden. The dataset consisted of 9765 deceased subjects with CSF measures, including 93 with CJD, whereof 56% autopsy verified. Results: Patients who later died of CJD had elevated CSF T-tau and T-tau/P-tau ratio, but not CSF P-tau, compared to all other dementia patients and compared to patients who died of Alzheimer’s disease (AD). The previously defined biomarker profile had a specificity of 99.0%, a sensitivity of 78.5% and a positive likelihood ratio (LR+) of 79.9. When tested against common differential diagnoses, the sensitivity, specificity and LR+ of this profile was 78.5%, 99.6% and 196.6 in relation to AD, and 78.5%, 99.3% and 109.3 in relation to other dementias. In CJD subjects (n=30) with repeated measurements, but not in subjects with AD (n=242) or other dementias (n=258), T-tau and T-tau/P-tau ratios increased over time. Conclusion: In this clinical routine setting, the combination of increased T-tau levels and increased T-tau/P-tau ratios in CJD patients has a very high specificity against important differential diagnoses to CJD, and may serve as a clinically useful diagnostic test.Background: Distinguishing the invariably lethal prion disease Creutzfeldt-Jakob disease (CJD) from non-prion rapidly progressive dementias is important and sometimes difficult, and reliable tools for diagnosis are thus in great demand. Cerebrospinal fluid (CSF) levels of total tau (T-tau) and phosphorylated tau (P-tau) have been used to identify patients with CJD in small studies. Here, we wanted to validate the diagnostic performance of CSF T-tau, P-tau and the T-tau/P-tau-ratio by analyzing results from a large database of clinical routine samples, in combination with diagnosis information from the Swedish mortality registry. Methods: We cross-referenced the Swedish mortality registry with a dataset of CSF measurements of T-tau and P-tau performed in clinical routine at the Clinical Neurochemistry Laboratory of the Sahlgrenska University Hospital, serving most of Sweden. The dataset consisted of 9765 deceased subjects with CSF measures, including 93 with CJD, whereof 56% autopsy verified. Results: Patients who later died of CJD had elevated CSF T-tau and T-tau/P-tau ratio, but not CSF P-tau, compared to all other dementia patients and compared to patients who died of Alzheimer’s disease (AD). The previously defined biomarker profile had a specificity of 99.0%, a sensitivity of 78.5% and a positive likelihood ratio (LR+) of 79.9. When tested against common differential diagnoses, the sensitivity, specificity and LR+ of this profile was 78.5%, 99.6% and 196.6 in relation to AD, and 78.5%, 99.3% and 109.3 in relation to other dementias. In CJD subjects (n=30) with repeated measurements, but not in subjects with AD (n=242) or other dementias (n=258), T-tau and T-tau/P-tau ratios increased over time. Conclusion: In this clinical routine setting, the combination of increased T-tau levels and increased T-tau/P-tau ratios in CJD patients has a very high specificity against important differential diagnoses to CJD, and may serve as a clinically useful diagnostic test.