MRI and fluid biomarkers reveal determinants of myelin and axonal loss with aging

Abstract

Objective: White matter damage is a feature of Alzheimer's disease, yet little is known about how facets of the Alzheimer's disease process relate to key features of white matter structure. We examined the association of Alzheimer's disease (Aß 42/40 ratio; pTau181), neuronal injury (NfL), and reactive astrogliosis (GFAP) biomarkers with MRI measures of myelin content and axonal density. Methods: Among cognitively normal participants in the BLSA and GESTALT studies who received MRI measures of myelin content (defined by myelin water fraction [MWF]) and axonal density (defined by neurite density index [NDI]), we quantified plasma levels of Ab 42 , Ab 40 , pTau181, NfL, and GFAP. Linear regression models adjusted for demographic variables were used to relate these plasma biomarker levels to the MRI measures. Results: In total, 119 participants received MWF imaging (age: 56 [SD 21]), of which 43 received NDI imaging (age: 50 [SD 18]). We found no relationship between plasma biomarkers and total brain myelin content. However, secondary analysis found higher GFAP was associated with lower MWF in the temporal lobes (ß = À0.13; P = 0.049). Further, higher levels of NfL (ß = À0.22; P = 0.009) and GFAP (ß = À0.29; P = 0.002) were associated with lower total brain axonal density. Secondary analyses found lower Ab 42/40 ratio and higher pTau181 were also associated with lower axonal density, but only in select brain regions. These results remained similar after additionally adjusting for cardiovascular risk factors. Interpretation: Plasma biomarkers of neuronal injury and astrogliosis are associated with reduced axonal density and region-specific myelin content. Axonal loss and demyelination may co-occur with neurodegeneration and astrogliosis ahead of clinically meaningful cognitive decline.

Alzheimer’s Disease-Related Phospho-Tau181 Signals Are Localized to Demyelinated Axons of Parvalbumin-Positive GABAergic Interneurons in an App Knock-In Mouse Model of Amyloid-β Pathology

“…A previous study has reported a relationship between myelin water fraction (MWF), a surrogate of myelin content, and p-tau181/Aβ 42 ratio in the CSF from preclinical AD patients, in which higher levels of p-tau181/Aβ 42 resulted in an increased decline in MWF with age [ 63 ]. Also, elevated plasma p-tau181 has been associated with lower axonal density quantified by MWF in the occipital lobe [ 64 ]. These reports suggest that increased levels of fluid p-tau181 correlate with reduced myelin content in human brains.…”

Relationship between baseline plasma p‐tau181 and longitudinal changes in cognition and structural brain measures in a cohort of cognitively unimpaired older adults

“…However, further studies are needed to investigate these patterns of change in other structural brain measures and their relationship to plasma p‐tau181. Also, investigating the association of these measures with glial fibrillary acidic protein (GFAP), a product of astroglial activation and astrocytosis, might clarify these findings, as this biomarker has been associated with incipient axonal loss in CU individuals 1,2,15,46 . Another possible explanation is that older adults with reduced cortical thickness and hippocampal atrophy are more closely related to clinically significant cognitive impairment.…”

Hypertensive Adults Exhibit Lower Myelin Content: A Multicomponent Relaxometry and Diffusion Magnetic Resonance Imaging Study

“…We used the signal model explicitly accounting for nonzero TE. 6,16,20 This emerging method offers rapid and reliable whole-brain MWF map within feasible clinical time 6,16,20,[31][32][33][34] and has been used in assessing myelin loss in mild cognitive impairment and dementias, as well as examining factors influencing cerebral myelination in normative aging. 16,22,23,26,[32][33][34][35][36][37][38][39][40][41][42][43][44][45] A whole-brain R1 map was also generated from the co-registered SPGR and DAM datasets using DESPOT1, 21 and a wholebrain R2 map was generated from the co-registered bSSFP and DAM datasets using DESPOT2.…”

“…6,16,20 This emerging method offers rapid and reliable whole-brain MWF map within feasible clinical time 6,16,20,[31][32][33][34] and has been used in assessing myelin loss in mild cognitive impairment and dementias, as well as examining factors influencing cerebral myelination in normative aging. 16,22,23,26,[32][33][34][35][36][37][38][39][40][41][42][43][44][45] A whole-brain R1 map was also generated from the co-registered SPGR and DAM datasets using DESPOT1, 21 and a wholebrain R2 map was generated from the co-registered bSSFP and DAM datasets using DESPOT2. 21 The DW images were corrected for eddy current using the function eddy in FSL and for motion effects using the affine registration tools as implemented in FSL 30 and registered to the DW image obtained with b=0 s/mm 2 using FNIRT.…”