CSF biomarker associations with change in hippocampal volume and precuneus thickness: Implications for the Alzheimer's pathological cascade

Psychology Service, VA Boston Healthcare System, Boston, MA, USA, .
Brain Imaging and Behavior (Impact Factor: 4.6). 05/2012; 6(4). DOI: 10.1007/s11682-012-9171-6
Source: PubMed

ABSTRACT Neurofibrillary tangles (NFT) and amyloid plaques are hallmark neuropathological features of Alzheimer's disease (AD). There is some debate as to which neuropathological feature comes first in the disease process, with early autopsy studies suggesting that NFT develop first, and more recent neuroimaging studies supporting the early role of amyloid beta (Aβ) deposition. Cerebrospinal fluid (CSF) biomarkers of Aβ(42) and hyperphosphorylated tau (p-tau) have been shown to serve as in vivo proxy measures of amyloid plaques and NFT, respectively. The aim of this study was to examine the association between CSF biomarkers and rate of atrophy in the precuneus and hippocampus. These regions were selected because the precuneus appears to be affected early and severely by Aβ deposition, and the hippocampus similarly by NFT pathology. We predicted (1) baseline Aβ(42) would be related to accelerated rate of cortical thinning in the precuneus and volume loss in the hippocampus, with the latter relationship expected to be weaker, (2) baseline p-tau(181p) would be related to accelerated rate of hippocampal atrophy and cortical thinning in the precuneus, with the latter relationship expected to be weaker. Using all ADNI cohorts, we fitted separate linear mixed-effects models for changes in hippocampus and precuneus longitudinal outcome measures with baseline CSF biomarkers modeled as predictors. Results partially supported our hypotheses: Both baseline p-tau(181p) and Aβ(42) were associated with hippocampal atrophy over time. Neither p-tau(181p) nor Aβ(42) were significantly related to cortical thinning in the precuneus over time. However, follow-up analyses demonstrated that having abnormal levels of both Aβ(42) and p-tau(181p) was associated with an accelerated rate of atrophy in both the hippocampus and precuneus. Results support early effects of Aβ in the Alzheimer's disease process, which are less apparent than and perhaps dependent on p-tau effects as the disease progresses. However, amyloid deposition alone may be insufficient for emergence of significant morphometric changes and clinical symptoms.

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Available from: Hiroko Hayama Dodge, Aug 14, 2015
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    • "In the cascade model [1] [2], the capacity of each biomarker to predict cognitive decline depends on the stage of AD disease process (e.g., normal, early mild cognitive impairment [MCI], late MCI, or AD), and whether biomarker baseline values or biomarker progressions are used. It is likely, for example, that brain beta amyloid burden is already high and probably plateaus by the time of AD diagnosis [3] [4], and although brain amyloid burden may distinguish among subjects with AD, MCI, and normal subjects cross-sectionally, continuing declines in cognitive functions at late MCI or AD stages will not be related to brain amyloid burden. Although baseline biomarker values are examined often in relation with subsequent longitudinal cognitive or functional trajectories, there is a paucity of data regarding biomarker progressions and their associations with cognitive or functional trajectories. "
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