Imaging and cerebrospinal fluid biomarkers in early preclinical alzheimer disease

ObjectiveDeposition of amyloid (A)-containing plaques as evidenced by amyloid imaging and cerebrospinal fluid (CSF) A1-42 (A42) is an early indicator of preclinical Alzheimer disease (AD). To better understand their relationship during the earliest preclinical stages, we investigated baseline CSF markers in cognitively normal individuals at different stages of amyloid deposition defined by longitudinal amyloid imaging with Pittsburgh compound B (PIB): (1) PIB-negative at baseline and follow-up (PIB-; normal), (2) PIB-negative at baseline but PIB-positive at follow-up (PIB converters; early preclinical AD), and (3) PIB-positive at baseline and follow-up (PIB+; preclinical AD). MethodsCognitively normal individuals (n=164) who had undergone baseline PIB scan and CSF collection within 1 year of each other and at least 1 additional PIB follow-up were included. Amyloid status was defined dichotomously using an a priori mean cortical cutoff. ResultsPIB converters (n=20) at baseline exhibited significantly lower CSF A42 compared to those who remained PIB-negative (n=123), but higher compared to the PIB+ group (n=21). A robust negative correlation (r=-0.879, p=0.0001) between CSF A42 and absolute (but subthreshold) PIB binding was observed during this early preclinical stage. The negative correlation was not as strong once individuals were PIB-positive (r=-0.456, p=0.038), and there was no correlation in the stable PIB- group (p=0.905) or in the group (n=10) with early symptomatic AD (p=0.537). InterpretationCSF A42 levels are tightly coupled with cortical amyloid load in the earliest stages of preclinical AD, and begin to decrease dramatically prior to the point when an abnormal threshold of cortical accumulation is detected with amyloid imaging. Ann Neurol 2016;80:379-387