Background: White matter hyperintensities (WMH) are prevalent in dementia, but lesion volume does not capture their microstructural heterogeneity. The T1-weighted to fluid-attenuated inversion recovery (T1w/T2w-FLAIR) ratio is sensitive to myelin, gliosis, and tissue water. We tested whether lesion-specific T1w/T2w-FLAIR ratio, referenced to each participant's normal-appearing white matter (NAWM), differs by diagnosis and reflects distinct amyloid and vascular mechanisms in Alzheimer's disease (AD) and vascular dementia (VD). Methods: We analyzed 576 participants from the multicentre BICWALZS cohort (seven South Korean sites), spanning subjective cognitive impairment (SCI, n=71), mild cognitive impairment (n=270), AD (n=125) and VD (n=88). WMH T1w/T2w-FLAIR ratio was regressed on NAWM ratio, yielding standardized residuals as the outcome. Regression and mediation models tested diagnosis, plasma biomarkers, APOE genotype, amyloid PET and vascular risk burden, adjusting for age, sex, education and site. We conducted regression and mediation analyses after multiple imputation for missing variables. We adjusted for hierarchical models using Bonferroni correction. We tested for insensitivity to site effects by applying ComBat harmonization. Results: Older age, AD, VD, and high vascular risk burden were associated with higher residualized T1w/T2w-FLAIR ratios relative to SCI. Lower plasma amyloid-beta 42 (greater amyloid burden) was associated with lower T1w/T2w-FLAIR ratios. Greater vascular burden was associated with greater T1w/T2w-FLAIR ratios, which partially mediated the VD association with T1w/T2w-FLAIR. Lower amyloid-beta 42 (greater amyloid) was associated with lower T1w/T2w-FLAIR, which partially mediated the effect between AD and T1w/T2w-FLAIR ratio. Findings were robust to harmonization. Conclusions: Residualized WMH T1w/T2w-FLAIR ratio captures lesion-specific microstructural variation missed by volumetric measures, consistent with vascular-gliotic injury in VD and coexisting amyloid-linked demyelination in AD. Limitations include the cross-sectional design, no cognitively normal comparison group, and a predominantly Korean sample.
Rushil Srirambhatla, J. Campion, Thomas Desmidt et al.· medRxiv· 0 citations
Summary Background Reduced [18F]Fluorodeoxyglucose ([18F]FDG)-PET uptake is a core imaging feature of Alzheimer's disease (AD). While tau load correlates with this metabolic signature, it remains unclear whether the spatial extent of tauopathy (SEOT) more accurately explains brain glucose hypometabolic patterns. Here, we compared SEOT versus tau load to determine their ability to predict brain hypometabolic signatures in AD. Methods We performed a cross-sectional study of amyloid-β positive participants from ADNI (n = 150) and an atypical AD subset from the McGill University Research Centre for Studies in Ageing (MCSA; n = 44). Participants underwent [18F]AV1451 or [18F]MK6240 tau-PET and [18F]FDG-PET. Tau load was indexed with regional SUVR, and SEOT with the proportion of abnormal voxels. Linear regressions related temporal and whole-cortex tau-PET load or SEOT to [18F]FDG-PET. We also compared the accuracy of tau-PET metrics for identifying AD-like hypometabolism. Spearman correlations assessed SEOT/tau load-FDG associations at regional and network levels. Partial Least Squares (PLS) regression investigated whether distributed tau load and SEOT predicted [18F]FDG-PET signatures. Structural equation modelling and hierarchical linear models assessed associations between tau metrics and cognition dependent and independent of [18F]FDG-PET. Findings Whole-cortex SEOT best predicted decreased signal in the [18F]FDG-PET AD-meta-ROI. SEOT also performed better in classifying AD-related brain hypometabolism. Across regions and networks, SEOT performed similarly or better than tau load in predicting metabolic dysfunction. Voxelwise analyses suggested complementary predictive value of SEOT and tau load, each capturing slightly distinct spatial associations with [18F]FDG-PET. PLS demonstrated partially non-redundant contributions from tau load and SEOT. Cortical SEOT showed the strongest predictive value for cognition. Interpretation SEOT provides complementary, independent, and often stronger predictive value than tau load for brain metabolism, particularly for network-level dysfunction. SEOT may improve diagnostic characterisation and prediction of cognitive impairment beyond [18F]FDG-PET. Funding TRIAD is supported by the Weston Brain Institute, Canadian Institutes of Health Research, Canadian Consortium of Neurodegeneration and Aging, Brain Canada Foundation, the Fonds de Recherche du Québec – Santé, and the Colin J Adair Charitable Foundation. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and the Canadian Institutes of Health Research.
Arthur C. Macedo, Lydia Trudel, S. A. Hosseini et al.· EBioMedicine· 0 citations
In low- and middle-income countries, Alzheimer’s disease (AD) constitutes a growing public health burden. However, AD biomarkers research remains underrepresented in African populations. This study assesses core biomarkers of AD and their relevance in the African context as potential aid in clinical diagnosis. Nigerian older adults from VALIANT cohort (n = 967) underwent biomarker quantification in plasma (p-tau217, GFAP, NfL, Aβ42 and Aβ40) employing both the Single Molecule Assay (Simoa, Quanterix) and Nucleic acid-Linked Immuno-Sandwich Assay (NULISA, Alamar). Biomarkers were associated with disease severity in clinical-diagnostic and clinical-biological groups, with stepwise increases of p-tau217, NfL and GFAP from cognitively unimpaired to dementia (p < 0.05). Results were consistent across platforms. Comparison between sexes showed higher biomarker levels in male participants across diagnostic groups. A significant effect of apoE-E4 proteotype on p-tau217 levels, after adjusting for age and sex was identified. These findings support the application of plasma AD biomarkers in the African context and the relevance of further AD biomarker research in diverse populations.
T. Akinyemi, I. Pola, K. Tan et al.· npj Dementia· 0 citations
In Aβ-negative cognitively impaired individuals with high cerebrovascular burden, elevated plasma GFAP is associated with medial temporal atrophy and cognitive decline, suggesting GFAP may capture astrocyte-reactivity relevant to vascular cognitive impairment beyond amyloid pathology.
M. S. Oliveira-Junior, M. Rodrigues, Livia Amaral et al.· Neurology· 0 citations
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