Abstract
PurposeRecent evidence suggests that PET imaging with amyloid-β (Aβ) tracers can be used to assess myelin integrity in cerebral white matter (WM). Alzheimer’s disease (AD) is characterized by myelin changes that are believed to occur early in the disease course. Nevertheless, the extent to which demyelination, as measured with Aβ PET, contributes to AD progression remains unexplored.MethodsParticipants with concurrent 18F-florbetapir (FBP) PET, MRI, and cerebrospinal fluid (CSF) examinations were included (241 cognitively normal, 347 Aβ-positive cognitively impaired, and 207 Aβ-negative cognitively impaired subjects). A subset of these participants had also available diffusion tensor imaging (DTI) images (n = 195). We investigated cross-sectional associations of FBP retention in the white matter (WM) with MRI-based markers of WM degeneration, AD clinical progression, and fluid biomarkers. In longitudinal analyses, we used linear mixed models to assess whether FBP retention in normal-appearing WM (NAWM) predicted progression of WM hyperintensity (WMH) burden and clinical decline.ResultsIn AD-continuum individuals, FBP retention in NAWM was (1) higher compared with WMH regions, (2) associated with DTI-based measures of WM integrity, and (3) associated with longitudinal progression of WMH burden. FBP uptake in WM decreased across the AD continuum and with increasingly abnormal CSF biomarkers of AD. Furthermore, FBP retention in the WM was associated with large-calibre axon degeneration as reflected by abnormal plasma neurofilament light chain levels. Low FBP uptake in NAWM predicted clinical decline in preclinical and prodromal AD, independent of demographics, global cortical Aβ, and WMH burden. Most of these associations were also observed in Aβ-negative cognitively impaired individuals.ConclusionThese results support the hypothesis that FBP retention in the WM is myelin-related. Demyelination levels progressed across the AD continuum and were associated with clinical progression at early stages, suggesting that this pathologic process might be a relevant degenerative feature in the disease course.
Highlights
MethodsOver the past decades, Alzheimer’s disease (AD) has been conceptualized as a grey matter pathology characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles [1, 2]
Low FBP uptake in the white matter (WM) correlates with abnormal cerebrospinal fluid (CSF) and plasma biomarkers Consistent with previous section findings of progressive demyelination along the AD continuum, we found that low adjusted standardized uptake value ratio (SUVR) in both normal-appearing WM (NAWM) and WM hyperintensity (WMH) was associated with more pathological CSF Aβ-42 and p-tau181 levels only among subjects in the AD continuum (A+) (Fig. 4)
We explored the associations of demyelination, as reflected by low FBP retention in cerebral WM, with MRI markers of WM integrity, AD fluid biomarkers, and disease progression
Summary
MethodsOver the past decades, Alzheimer’s disease (AD) has been conceptualized as a grey matter pathology characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles [1, 2]. Numerous neuropathological and neuroimaging studies indicate that white matter (WM) abnormalities are commonly present among AD patients [3,4,5,6,7,8] While these findings have been traditionally interpreted as comorbidities, accumulating evidence from our group [9] and others [10,11,12,13,14] points towards a link between WM pathology and AD-specific neuropathologic changes, suggesting that WM degeneration is a characteristic feature of the AD pathological cascade. The aforementioned results have been only reported in multiple sclerosis and aging, and the association of demyelination, as measured with Aβ PET, with pathologic features and progression in AD has not yet been investigated
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