Mattsson N, Insel PS, Donohue M, Jagust W, Sperling R, Aisen P, Weiner MW, Alzheimer’s Disease Neuroimaging Initiative. Predicting Reduction of Cerebrospinal Fluid β-Amyloid 42 in Cognitively Healthy Controls. JAMA Neurol. 2015 May;72(5):554-60. PubMed.

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  1. These findings by Mattsson and colleagues are consistent with recent reports that cognitively normal elderly with PIB retention close to the cutoff at baseline were more likely to show higher rates of retention on follow-up scans than those with low baseline retention. The initial Aβ CSF cutoffs were based on autopsies of patients with dementia and may be too high to determine risk for AD in individuals in earlier stages of the disease process. Further, higher p-tau values predict decline in CSF Aβ, and the combination of low baseline Aβand high p-tau was the best predictor of decline. It is not clear if they tested the total tau/Aβ ratio or p-tau/Aβ ratio to predict decline as measured by Shaw et al. (Shaw et al., 2009). High baseline CSF tau and p-tau may be important predictors of clinical decline in Aβ-positive amnestic MCI (Buchhave et al., 2012). The findings from the Mattsson study have implications for developing risk profiles and determining eligibility for intervention in preclinical AD. Study limitations include a small sample size, low E4 carrier rate, and the term “decliner” probably should be changed to “who declines below cut-off,” as some individuals with high baseline Aβ also demonstrated decline in CSF values. Finally, it is interesting to note that six decliners and two non-decliners had amyloid PET during the follow-up period, and none were PET positive.

    View all comments by Stephen Salloway

  2. Whilst the numbers are relatively small, this is a valuable study providing a rare opportunity to study the CSF profiles of healthy elderly individuals as they change over time. The principal finding—that individuals with initially low-normal CSF Aβ42 were most likely to decline to “pathological” levels of CSF Aβ42—is of considerable interest, suggesting a potential strategy for enriching clinical trials aiming to recruit amyloid accumulators. It will be of particular interest to follow these individuals to see if, as expected, they develop cognitive impairment; and if so, over what time frame. This study also highlights the potential value of adopting biomarker “gray zones” either in place of, or as well as, a single cutoff point for CSF Aβ42, or other biomarkers. This may be both a more biological plausible way of classifying individuals in the border zone between normal and abnormal, and, as this study demonstrates, a potential means of highlighting those at greatest risk of future decline.

    View all comments by Jonathan Schott

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