Added value of CSF multi-marker analysis in diagnosis and progression of dementia.

Recently, some emerging cerebrospinal fluid (CSF) markers have been proposed as biomarkers for Alzheimer disease (AD) that can have an effect on disease progression. We analyze the accuracy of these CSF markers for diagnosis of AD in reference to brain Amyloid-PET. We also investigated whether they help in differentiating AD from other dementias and examine their influence in tracing the progression to dementia. Amyloid-β (Aβ) 1-42, total tau (t-tau), phosphorylated tau, Aβ40 , Aβ38 , Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE-1), neurogranin (ng), phosphorylated-heavy-chain neurofilament, and α-synuclein (α-syn) CSF levels were analyzed in 319 subjects, among whom 57 also underwent an Amyloid-PET scan. We also analyzed longitudinal clinical data from 239 subjects. Emerging CSF markers, especially ng/BACE-1 ratio (AUC=0.77) and their combinations with core-AD CSF markers (all AUCs > 0.85), showed high accuracy to discriminate Amyloid-PET positivity. Subjects with AD had higher CSF BACE-1, ng and α-syn levels than those with non-AD dementia. Interestingly, CSF t-tau/α-syn ratio was higher in subjects with dementia with Lewy bodies than in those with frontotemporal dementia. Most emerging/core-AD ratios predicted a faster conversion from MCI stage to AD and appeared to be helpful when core-AD CSF markers were discordant. In addition, the rate of cognitive decline was associated with all CSF core-AD biomarkers, several emerging/core-AD two-marker ratios and CSF ng levels. These results suggest that emerging biomarkers in conjunction with core-AD markers improve diagnosis of AD, are associated with the conversion from MCI into AD and predict a faster progression of dementia.