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Altered T1w/T2w-FLAIR Ratio in White Matter Hyperintensities as an Indicator of Structural Integrity Loss: Association with Alzheimer’s Disease and Vascular Dementia
Srirambhatla R, Campion J, Desmidt T, Pan Y, Andreescu C, Ferreira PC, Povala G, Bellaver B et al.. medRxiv, 2026-07-30
Topic: Plasma and spinal-fluid biomarkers
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.
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APA 7th
Srirambhatla, R., Campion, J., Desmidt, T., Pan, Y., Andreescu, C., Ferreira, P. C., et al. (2026). Altered T1w/T2w-FLAIR Ratio in White Matter Hyperintensities as an Indicator of Structural Integrity Loss: Association with Alzheimer’s Disease and Vascular Dementia. medRxiv. https://doi.org/10.64898/2026.07.28.26359139
Vancouver
Srirambhatla R, Campion J, Desmidt T, Pan Y, Andreescu C, Ferreira PC, et al. Altered T1w/T2w-FLAIR Ratio in White Matter Hyperintensities as an Indicator of Structural Integrity Loss: Association with Alzheimer’s Disease and Vascular Dementia. medRxiv. 2026. doi:10.64898/2026.07.28.26359139.
BibTeX
@article{srirambhatla2026-b5f25332,
author = {Srirambhatla, R. and Campion, J. and Desmidt, T. and Pan, Y. and Andreescu, C. and Ferreira, P. C. and Povala, G. and Bellaver, B. and others},
title = {{Altered T1w/T2w-FLAIR Ratio in White Matter Hyperintensities as an Indicator of Structural Integrity Loss: Association with Alzheimer’s Disease and Vascular Dementia}},
journal = {medRxiv},
year = {2026},
doi = {10.64898/2026.07.28.26359139},
url = {https://doi.org/10.64898/2026.07.28.26359139}
}
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Key findings
- 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.
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Study details
- Study designcross-sectional
- Participants71
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 37 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for effect reported and randomized / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 23 of the 62 points we could judge it on, which is 37 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 4 / 12 | A snapshot of people at one point in time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 1 / 4 | 71 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 23 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 23 of the 62 points we could judge it on is 37 out of 100. |
| Total | 37 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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