The Brain Chart of Aging: Machine‐learning analytics reveals links between brain aging, white matter disease, amyloid burden, and cognition in the iSTAGING consortium of 10,216 harmonized MR scans

Habes, Mohamad; Pomponio, Raymond; Shou, Haochang; Doshi, Jimit; Mamourian, Elizabeth; Erus, Güray; Nasrallah, Ilya M.; Launer, Lenore J.; Rashid, Tanweer; Bilgel, Murat; Fan, Yong; Toledo, Jon B.; Yaffe, Kristine; Sotiras, Aristeidis; Srinivasan, Dhivya; Espeland, Mark A.; Masters, Colin L.; Maruff, Paul; Fripp, Jürgen; Völzk, Henry; Johnson, Sterling C.; Morris, John C.; Albert, Marilyn; Miller, Michael I.; Bryan, R. Nick; Grabe, Hans J.; Resnick, Susan M.; Wolk, David A.; Davatzikos, Christos

doi:10.1002/alz.12178

Cited by 126 publications

(118 citation statements)

References 43 publications

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“…Nevertheless, numerous neuropathological and neuroimaging studies indicate that white matter (WM) abnormalities are also 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. Among these pathological changes, one of the most prominent is the generalized degradation of axonal myelin sheets in cerebral WM [15][16][17].…”

Section: Introductionmentioning

confidence: 98%

18F-florbetapir PET as a marker of myelin integrity across the Alzheimer’s disease spectrum

Moscoso

Silva‐Rodríguez²,

Aldrey

et al. 2021

Eur J Nucl Med Mol Imaging

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Purpose Recent 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. Methods Participants 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. Results In 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. Conclusion These 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.

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Section: Introductionmentioning

confidence: 98%

18F-florbetapir PET as a marker of myelin integrity across the Alzheimer’s disease spectrum

Moscoso

Silva‐Rodríguez²,

Aldrey

et al. 2021

Eur J Nucl Med Mol Imaging

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“… 1 , 2 , 4 White matter hyperintensities are associated with an increased risk of dementia, cognitive decline, stroke, death, abnormal gait, disturbed balance, and depression. 1 , 2 , 4 , 6 , 7 Habes et al 5 , 8 reported higher WMH burden to be associated with advanced brain aging and increased brain atrophy patterns related to Alzheimer disease (AD) in the Study of Health in Pomerania (SHIP). A recent longitudinal study 9 reported associations between greater WMH burden and accelerated cognitive, neuropsychiatric, and functional decline independent of traditional AD risk factors and MRI biomarkers.…”

Section: Introductionmentioning

confidence: 99%

Association Between Obstructive Sleep Apnea and Brain White Matter Hyperintensities in a Population-Based Cohort in Germany

et al. 2021

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IMPORTANCEUnderlying pathomechanisms of brain white matter hyperintensities (WMHs), commonly observed in older individuals and significantly associated with Alzheimer disease and brain aging, have not yet been fully elucidated. One potential contributing factor to WMH burden is chronic obstructive sleep apnea (OSA), a disorder highly prevalent in the general population with readily available treatment options. OBJECTIVE To investigate potential associations between OSA and WMH burden. DESIGN, SETTING, AND PARTICIPANTS Analyses were conducted in 529 study participants of the Study of Health in Pomerania-Trend baseline (SHIP-Trend-0) study with complete WMH, OSA, and important clinical data available. SHIP-Trend-0 is a general population-based, cross-sectional, observational study to facilitate the investigation of a large spectrum of common risk factors, subclinical disorders, and clinical diseases and their relationships among each other with patient

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“…Nevertheless, numerous neuropathological and neuroimaging studies indicate that white matter (WM) abnormalities are also commonly present among AD patients [3][4][5][6][7][8]. While these ndings 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-speci c neuropathologic changes, suggesting that WM degeneration is a characteristic feature of the AD pathological cascade. Among these pathological changes, one of the most prominent is the generalized degradation of axonal myelin sheets in cerebral WM [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

18F-florbetapir PET as a marker of myelin integrity across the Alzheimer’s disease spectrum

Moscoso¹,

Silva‐Rodríguez²,

Aldrey³

et al. 2021

Preprint

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Purpose: Recent evidence suggest 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.Methods: Participants with concurrent 18F-florbetapir (FBP), 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 CSF 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. Results: In AD-continuum individuals, FBP retention in NAWM was 1) higher compared to 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.Conclusion: These results support the hypothesis that FBP retention in the WM is myelin-dependent. 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.

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The Brain Chart of Aging: Machine‐learning analytics reveals links between brain aging, white matter disease, amyloid burden, and cognition in the iSTAGING consortium of 10,216 harmonized MR scans

Cited by 126 publications

References 43 publications

18F-florbetapir PET as a marker of myelin integrity across the Alzheimer’s disease spectrum

18F-florbetapir PET as a marker of myelin integrity across the Alzheimer’s disease spectrum

Association Between Obstructive Sleep Apnea and Brain White Matter Hyperintensities in a Population-Based Cohort in Germany

18F-florbetapir PET as a marker of myelin integrity across the Alzheimer’s disease spectrum

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