P4–059: Amyloid imaging and CSF biomarkers in predicting cognitive impairment up to 7.5 years later

Abstract

Objectives: We compared the ability of molecular biomarkers for Alzheimer disease (AD), including amyloid imaging and CSF biomarkers (Ab 42 , tau, ptau 181 , tau/Ab 42 , ptau 181 /Ab 42 ), to predict time to incident cognitive impairment among cognitively normal adults aged 45 to 88 years and followed for up to 7.5 years.Methods: Longitudinal data from Knight Alzheimer's Disease Research Center participants (N 5 201) followed for a mean of 3.70 years (SD 5 1.46 years) were used. Participants with amyloid imaging and CSF collection within 1 year of a clinical assessment indicating normal cognition were eligible. Cox proportional hazards models tested whether the individual biomarkers were related to time to incident cognitive impairment. "Expanded" models were developed using the biomarkers and participant demographic variables. The predictive values of the models were compared.Results: Abnormal levels of all biomarkers were associated with faster time to cognitive impairment, and some participants with abnormal biomarker levels remained cognitively normal for up to 6.6 years. No differences in predictive value were found between the individual biomarkers (p . 0.074), nor did we find differences between the expanded biomarker models (p . 0.312). Each expanded model better predicted incident cognitive impairment than the model containing the biomarker alone (p , 0.005). Conclusions:Our results indicate that all AD biomarkers studied here predicted incident cognitive impairment, and support the hypothesis that biomarkers signal underlying AD pathology at least several years before the appearance of dementia symptoms. Biomarkers may signal underlying Alzheimer disease (AD) pathology a decade or more before the appearance of dementia symptoms.1,2 Therefore, understanding the temporal relationships between biomarker levels in cognitively normal adults, symptomatic AD (i.e., incident AD), and factors that modify those relationships is imperative.3 The National Institute on Aging/ Alzheimer's Association workgroup urges that the factors that best predict progression from normal cognition to cognitive impairment and dementia due to AD need to be determined. 3The most well-studied and promising molecular biomarkers of AD are those that reflect the presence of the signature lesions of AD: plaques, which comprise the amyloid-b (Ab) protein, and tangles, which comprise the tau protein. Both amyloid imaging, 4 used to identify fibrillar Ab plaques, and CSF biomarkers, 5 which reflect soluble Ab, tau, and phosphorylated tau (ptau), predict incident AD.6-8 However, until now, directly comparing the predictive ability of amyloid imaging with CSF biomarkers was difficult, given the recent development of amyloid imaging 4 and attendant short follow-up times, the lengthy hypothesized time between the appearance of AD

Ushering in the study and treatment of preclinical Alzheimer disease

“…Moreover, in the latter study, people with MCI who were positive for all of the three AD biomarkers consistently progressed to AD dementia during a 3-year period, whereas those with no positive biomarkers were unlikely to progress. These findings in MCI are supported by findings in cognitively normal individuals in which abnormal amyloid levels on PET imaging and CSF biomarkers, when examined together, are associated with faster time to cognitive impairment, whereas no differences were identified in the predictive value of individual biomarkers 174 .…”

Diagnostic Utility of Amyloid PET in Cerebral Amyloid Angiopathy-Related Symptomatic Intracerebral Hemorrhage

“…The age limit of 55 years for the young group was based on the previous studies showing no rise in amyloid tracer uptake until this age in large samples, [16][17][18][19][20][21] including ours. 22 The Cambridgeshire Regional Ethics Committee approved this study and all participants provided signed informed consent.…”

Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly

“…Several groups have demonstrated that PET measures of amyloid burden correlate well with CSF Ab42 measurements, and can be used in concert with other biomarkers as predictors of impending cognitive decline. [2][3][4] More recently, several promising PET radioligands for in vivo imaging of pathologic deposits of tau have been described. [5][6][7][8] As postmortem neurofibrillary tangle (NFT) burden is a predictor of global cognition 9 and CSF t-tau 10 and p-tau 11 improve the sensitivity and specificity of CSF Ab42 alone to identify those likely to progress to AD dementia, 2 in vivo imaging of tau pathology may represent a useful biomarker in clinical and translational AD research.…”

“…[2][3][4] More recently, several promising PET radioligands for in vivo imaging of pathologic deposits of tau have been described. [5][6][7][8] As postmortem neurofibrillary tangle (NFT) burden is a predictor of global cognition 9 and CSF t-tau 10 and p-tau 11 improve the sensitivity and specificity of CSF Ab42 alone to identify those likely to progress to AD dementia, 2 in vivo imaging of tau pathology may represent a useful biomarker in clinical and translational AD research. 18 F-T807 (T807, also known as 18 F AV1451) is a radioligand with high selectivity for pathologic tau aggregates (especially NFT pathology 5,12 ) over amyloid plaques, limited nonspecific white and gray matter binding, 5 and circumscribed off-target binding.…”