Diagnostic and prognostic value of cerebrospinal fluid SNAP-25 and neurogranin in Creutzfeldt-Jakob disease in a clinical setting cohort of rapidly progressive dementias

Abstract

Background The levels of synaptic markers synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng) have been shown to increase early in the cerebrospinal fluid (CSF) of patients with Creutzfeldt-Jakob disease (CJD) and to have prognostic potential. However, no validation studies assessed these biomarkers' diagnostic and prognostic value in a large clinical setting cohort of rapidly progressive dementia. Methods In this retrospective study, using commercially available immunoassays, we measured the levels of SNAP-25, Ng, 14–3-3, total-tau (t-tau), neurofilament light chain (NfL), and phospho-tau181 (p-tau) in CSF samples from consecutive patients with CJD (n = 220) or non-prion rapidly progressive dementia (np-RPD) (n = 213). We evaluated and compared the diagnostic accuracy of each CSF biomarker and biomarker combination by receiver operating characteristics curve (ROC) analyses, studied SNAP-25 and Ng CSF concentrations distribution across CJD subtypes, and estimated their association with survival using multivariable Cox regression analyses. Results CSF SNAP-25 and Ng levels were higher in CJD than in np-RPD (SNAP-25: 582, 95% CI 240–1250 vs. 115, 95% CI 78–157 pg/ml, p < 0.0001; Ng: 841, 95% CI 411–1473 vs. 390, 95% CI 260–766 pg/ml, p < 0.001). SNAP-25 diagnostic accuracy (AUC 0.902, 95% CI 0.873–0.931) exceeded that of 14–3-3 (AUC 0.853, 95% CI 0.816–0.889), t-tau (AUC 0.878, 95% CI 0.845–0.901), and the t-tau/p-tau ratio (AUC 0.884, 95% CI 0.851–0.916). In contrast, Ng performed worse (AUC 0.697, 95% CI 0.626–0.767) than all other surrogate biomarkers, except for NfL (AUC 0.649, 95% CI 0.593–0.705). SNAP-25 maintained a relatively high diagnostic value even for atypical CJD subtypes (AUC 0.792, 95% CI 0.729–0.854). In Cox regression analyses, SNAP-25 levels were significantly associated with survival in CJD (hazard ratio [HR] 1.71 95% CI 1.40–2.09). Conversely, Ng was associated with survival only in the most rapidly progressive CJD subtypes (sCJD MM(V)1 and gCJD M1) (HR 1.81 95% CI 1.21–2.93). Conclusions In the clinical setting, CSF SNAP-25 is a viable alternative to t-tau, 14–3-3, and the t-tau/p-tau ratio in discriminating the CJD subtypes from other RPDs. Additionally, SNAP-25 and, to a lesser extent, Ng predict survival in CJD, showing prognostic power in the range of CSF t-tau/14–3-3 and NfL, respectively.

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

“…A total of 11 patients were excluded from the survival analyses due to insufficient information on disease duration. Furthermore, the disease stage in the CJD subjects was calculated as the ratio between disease onset to sampling and the overall survival, as reported previously [11,18]. All np-RPD patients presented with RPD and tested negative by prion RT-QuIC.…”

“…Although sCJD is a common cause of rapidly progressive dementia (RPD), its early diagnosis and prognostication remain challenging due to heterogeneous clinical phenotypes and disease course. In recent years, the introduction of cerebrospinal fluid (CSF) biomarkers of neurodegeneration and prion pathology (i.e., the prion real-time quakinginduced conversion (RT-QuIC) assay) and brain magnetic resonance imaging (MRI) have dramatically improved the in vivo identification of sCJD patients and demonstrated some prognostic potential [3][4][5][6][7][8][9][10][11][12]. However, given the invasiveness of lumbar puncture (LP) and the specialised expertise required by these techniques (e.g., RT-QuIC or MRI), the identification of blood biomarkers for screening" prognostication and disease monitoring remains a research priority [13].…”

Tau, Glial Fibrillary Acidic Protein, and Neurofilament Light Chain as Brain Protein Biomarkers in Cerebrospinal Fluid and Blood for Diagnosis of Neurobiological Diseases

“…Each disease displays distinct clinical presentations, encompassing cognitive decline, behavioral changes, and movement disorders that are influenced by the specific Tau isoforms in the cell types and brain regions [22]. Alzheimer's disease (AD) 2.5 ± 1.3 [23] 318 [24]; 601 [25]; 604 [26] Parkinson's disease dementia (PDD) 3.1 [27] Creutzfeldt-Jakob disease (CJD) 9.0 [28] 2060 [26]; 6520 [28] Frontotemporal lobar degeneration (FTLD) 350 [26] Dementia with Lewy bodies (DLB) 305 [26] Vascular dementia (VaD) 238 [26] Corticobasal degeneration (CBD) 262 [26] Subjective memory complaints (SMC) 245 [26] Mild cognitive impairment (MCI) 246 [24]; 310 [25] p-Tau Normal 18 [24] Mild cognitive impairment (MCI) 22 [24]; 53 [25] Alzheimer's disease (AD) 29 [24]; 78 [25]; 83 [26] Frontotemporal lobar degeneration (FTLD) 47 [26] Dementia with Lewy bodies (DLB) 52 [26] Vascular dementia (VaD) 35 [26] Corticobasal degeneration (CBD) 50 [26] Progressive supranuclear palsy (PSP) 36 [26] Creutzfeldt-Jakob disease (CJD) 54 [26]; 61 [28] Psychiatric disorder (PSY) 41 [26] Subjective memory complaints (SMC) 45 [26] p-Tau181: Normal 2.6 ± 1.0 [23] p-Tau181: Alzheimer's disease (AD) 5.6 ± 2.0 [23] >65.5 (cutoff) [29] p-Tau231: Normal 7.5 ± 1.6 [23] p-Tau231: Alzheimer's disease (AD) 14.6 ± 6.1 [23] GFAP Normal 79.0 [25] 2175 [...…”