Abstract
Purpose: To test whether correcting for unspecific signal from the cerebral white matter increases the sensitivity of amyloid-PET for early stages of cerebral amyloidosis.Methods: We analyzed 18F-Florbetapir-PET and cerebrospinal fluid (CSF) Aβ42 data from 600 older individuals enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including people with normal cognition, mild cognitive impairment (MCI), and Alzheimer’s disease (AD) dementia. We determined whether three compartmental partial volume correction (PVC-3), explicitly modeling signal spill-in from white matter, significantly improved the association of CSF Aβ42 levels with global 18F-Florbetapir-PET values compared with standard processing without PVC (non-PVC) and a widely used two-compartmental PVC method (PVC-2). In additional voxel-wise analyses, we determined the sensitivity of PVC-3 compared with non-PVC and PVC-2 for detecting early regional amyloid build-up as modeled by decreasing CSF Aβ42 levels. For replication, we included an independent sample of 43 older individuals with subjective memory complaints from the INveStIGation of AlzHeimer’s PredicTors cohort (INSIGHT-preAD study).Results: In the ADNI sample, PVC-3 18F-Florbetapir-PET values normalized to whole cerebellum signal showed significantly stronger associations with CSF Aβ42 levels than non-PVC or PVC-2, particularly in the lower range of amyloid levels. These effects were replicated in the INSIGHT-preAD sample. PVC-3 18F-Florbetapir-PET data detected regional amyloid build-up already at higher (less abnormal) CSF Aβ42 levels than non-PVC or PVC-2 data.Conclusion: A PVC approach that explicitly models unspecific white matter binding improves the sensitivity of amyloid-PET for identifying the earliest stages of cerebral amyloid pathology which has implications for future primary prevention trials.
Highlights
Cerebrospinal fluid (CSF) concentrations of the 42-amino acidlong amyloid-β peptide (Aβ42) (Blennow et al, 2015) and amyloid-sensitive positron emission tomography (PET) tracers (Zhang et al, 2014; Martinez et al, 2017) serve as diseasedefining markers of Alzheimer’s disease (AD) in recently revised diagnostic research criteria (Jack et al, 2018)
Statistical testing using Steiger’s Z test on Fisher’ z transformed correlation coefficients revealed significantly higher negative correlations when using Partial volume effect correction (PVC)-3 SUVRWC values as compared to the standard processing without PVC, and this effect was pronounced in the lowest tertile (r = −0.34 for PVC-3 vs r = −0.01 for no PVC)
Amyloidsensitive PET tracers, including 18F-Florbetapir, show high unspecific binding in cerebral white matter (Schmidt et al, 2015). This leads to a proportionally higher confound of cortical amyloid signal at low levels of specific uptake so that accounting for this effect was expected to increase the sensitivity of 18F-Florbetapir-PET for early amyloid build-up. Consistent with this assumption, we found that 3-compartment PVC (Müller-Gärtner et al, 1992) of 18F-Florbetapir-PET SUVRWC values, taking spill-in of white matter signal into account, but not 2-compartmental PVC (Meltzer et al, 1996), significantly increased the association of 18F-Florbetapir-PET signal with CSF Aβ42 levels, and this effect was most pronounced within the lower range of global amyloid levels
Summary
Cerebrospinal fluid (CSF) concentrations of the 42-amino acidlong amyloid-β peptide (Aβ42) (Blennow et al, 2015) and amyloid-sensitive positron emission tomography (PET) tracers (Zhang et al, 2014; Martinez et al, 2017) serve as diseasedefining markers of Alzheimer’s disease (AD) in recently revised diagnostic research criteria (Jack et al, 2018). Due to the characteristically high non-specific white matter binding in amyloid-sensitive PET imaging the net PVE will depend on the actual cortical amyloid load: in early stage amyloidosis, when the actual cortical tracer concentration is relatively small, the measured signal will be highly influenced by Abbreviations: AD, Alzheimer’s disease; ADNI, Alzheimer’s Disease Neuroimaging Initiative; CSF, cerebrospinal fluid; FEW, family-wise error; INSIGHT-preAD, INveStIGation of AlzHeimer’s PredicTors cohort; MCI, mild cognitive impairment; MMSE, Mini Mental State Examination; MRI, magnetic resonance imaging; PET, positron emission tomography; PVC, partial volume effect correction; PVE, partial volume effect; SPM, Statistical Parametric Mapping; SUVR, standard uptake value ratio
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