Wu, Joseph C.

Abstract Background Cognitive impairment (CI) has diverse neurological etiologies, including Alzheimer’s Disease (AD), non-degenerative (ND) conditions, and cerebrospinal fluid (CSF) dynamic disorders, such as normal pressure hydrocephalus (NPH). The etiology of CI may be different to diagnose due to the overlap of non-specific symptoms. Various CSF biomarkers, such as amyloid beta (Aβ) 42, Aβ40, total Tau (t-Tau), and phosphorylated Tau 181 (p-Tau181), have been evaluated for their diagnostic utility in identifying the underlying cause for CI. Previous studies have suggested an isolated abnormal Aβ42 levels may be indicative of NPH in the appropriate clinical context. This study aims to further explore the clinical utility of AD-related CSF biomarkers to distinguish NPH from AD and ND causes of CI. Methods 240 patients were chart reviewed and categorized as either AD (n = 124), ND (n = 68), or NPH (n = 47) based on the etiologies of CI. Concentrations of Aβ40, Aβ42, t-Tau, p-Tau181 were measured in CSF (Cobas e601, Roche). Receiver operating characteristic (ROC) curves were plotted and optimal Youden cutoffs and areas under curve (AUCs) were calculated for each biomarker, and for selected ratios of biomarker combinations, for their ability to differentiate NPH from either AD or ND. Additionally, qualitative (abnormal/normal) result patterns for Aβ42, t-Tau, p-Tau181, and p-Tau181/Aβ42 ratio were reviewed for each patient, using established cut-offs for identifying AD (Aβ42≤1026 pg/mL, t-Tau>238 pg/mL, p-Tau181>21.7 pg/mL, p-Tau181/Aβ42>0.023). Results p-Tau181/Aβ42 ratio demonstrated one of the highest AUCs (0.931) to separate NPH from AD (sensitivity=84.8%, specificity= 91.9%), and Aβ42 showed the highest AUC (0.856) to separate NPH from ND (sensitivity=71.6%, specificity=89.7%). When using previously established AD cut-offs, the combination of an abnormally low Aβ42 along with a normal p-Tau181/Aβ42 ratio yielded a sensitivity of 40.4% and a specificity of 96.4% in distinguishing NPH from other CI etiologies in this cohort. In contrast, abnormal results for both Aβ42 and p-Tau181/Aβ42 ratio had a sensitivity of 89.5% and a specificity of 87.0% in identifying AD, while normal results for both biomarkers had a sensitivity of 91.2% and a specificity of 90.1% in identifying ND. Incorporating the qualitative results for t-Tau and p-Tau181 into the evaluation did not enhance the diagnostic performance for distinguishing NPH, AD or ND in this cohort. Conclusion ROC analysis indicated that p-Tau181/Aβ42 and Aβ42 may help differentiate NPH from AD and ND, respectively. However, the combination of an abnormally low Aβ42 and a normal p-Tau181/Aβ42 ratio, using current AD cut-offs, demonstrated a lower sensitivity but high specificity in distinguishing NPH from the other CI etiologies in this cohort, suggesting this result pattern may be used for NPH rule-in in patients with CI.