DIAGNOSTIC UTILITY OF CEREBROSPINAL FLUID BIOMARKERS IN IRISH SUBJECTS WITH COGNITIVE IMPAIRMENT

Abstract

CSF biomarkers have been recently implemented in Ireland for clinical use in subjects with cognitive impairment with several sites performing the CSF extraction and a single national reference laboratory carrying out the assay. To-date, there are no published data on their clinical utility for the differential diagnosis of Alzheimer's disease (AD) in Irish subjects. Retrospective cross-sectional study. Descriptive statistics were calculated for basic demographics and CSF biomarker results (Aβ42, total-tau (ttau), phosphorylated-tau (ptau), neurofilament light chain (NfL), analysed with currently available commercial kits), in a cohort of subjects with mild cognitive impairment (MCI), AD dementia, and controls. Single (Aβ42, ttau, ptau, NfL) and composite biomarkers (Aβ42/ptau ratio) receiver operating characteristics (ROC) curves were also calculated for the differential diagnosis of AD and controls. The sample comprised 93 subjects (46% males): 28 MCI (68±8.6 years, MMSE 26.7±2.4), 33 AD (67±9.4 years), MMSE 22±3.6) and 32 controls (65±8.1 years, MMSE 29.2±0.6). Aβ42 was lower in AD (388±146pg/ml) than in controls (736pg/ml, p<.001). Ttau and ptau levels were higher in AD (710±345pg/ml, 97±42pg/ml) than in controls (241±82pg/ml, 49±12pg/ml, p<.001). NfL levels (n=69) were highest in subjects with AD (1619±1100pg/ml) as compared with MCI (1100±750pg/ml) and controls (459±123pg/ml). 22/28 MCI had amnestic (single or multi-domain) phenotypes. 13/22 amnestic MCI and 2/6 non-amnestic MCI subjects had Aβ42 values lower than 500pg/ml. In the sample, ttau and ptau were correlated with each other (r=0.92), age (r=0.27, r=0.26) and MMSE (r=-0.6, r=-0.59) whereas NfL correlated with ptau (r=0.37), Aβ42(r= -0.39) and MMSE (r=-0.44). Diagnostic accuracy of CSF biomarkers for differentiating between AD and controls was higher for composite biomarkers (AUC Aβ42/ptau 0.957) as compared with individual biomarkers (AUC Aβ42 0.914, AUC ttau 0.932, AUC ptau 0.896). Interestingly, NfL outperformed individual core CSF biomarkers in differentiating between AD and controls (AUC 0.960). CSF biomarkers performed well in Irish subjects in differentiating subjects with dementia due to AD from controls and can be used for assessing underlying AD pathology in MCI subjects. Composite biomarkers behave better for clinical diagnostic purposes than single CSF biomarkers. NfL showed promising results, outperforming any other single biomarker.