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Underlying histopathology features of white matter hyperintensities in vascular and neurodegenerative disorders: a systematic review
Frigon E, Metz A, Parent O, Chadwick K, Kamal F, Alasmar Z, Brzezinski-Rittner A, Moqadam R et al.. Research Square, 2026-09-20
Topic: Plasma and spinal-fluid biomarkers
White matter hyperintensities (WMHs) are a hallmark of cerebral small vessel disease, commonly seen in cognitively normal older adults and patients with neurodegenerative disorders, and are thought to reflect varying degrees of tissue damage. Although FLAIR and T2-weighted MRI remain the best modalities for detecting WMHs, these lesions cannot be reliably distinguished macroscopically from normal appearing white matter, so standard neuropathology protocols do not specifically consider WMH regions unless MRI guidance is available. As a result, histopathological data on WMHs from gold-standard studies remain limited relative to their clinical prevalence. This review aimed to evaluate existing evidence linking MRI-defined WMHs to their underlying histopathology in postmortem brains from patients with various neurodegenerative disorders and aging controls. After a PubMed literature search and screening of abstracts and full texts, we included 45 articles: 10 on normal aging, 16 on Alzheimer's disease, 10 on vascular dementia, and 9 on related conditions. WMHs were histopathologically characterized by myelin loss (including spongiosis), axonal rarefaction, edema, dilated perivascular spaces, gliosis, arteriolosclerosis, and venous collagenosis, all indicative of underlying white matter pathology. The findings overall suggest that WMHs are pathologically heterogeneous, varying according to their anatomical location and distribution. Disease-specific differences in regional distribution, neuroinflammation, vascular pathology, and proteinopathy further contribute to their development and clinical significance, highlighting the need to consider both diagnosis and anatomical location when interpreting the pathological substrates of WMHs.
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APA 7th
Frigon, E., Metz, A., Parent, O., Chadwick, K., Kamal, F., Alasmar, Z., et al. (2026). Underlying histopathology features of white matter hyperintensities in vascular and neurodegenerative disorders: a systematic review. Research Square. https://doi.org/10.21203/rs.3.rs-11053221/v1
Vancouver
Frigon E, Metz A, Parent O, Chadwick K, Kamal F, Alasmar Z, et al. Underlying histopathology features of white matter hyperintensities in vascular and neurodegenerative disorders: a systematic review. Research Square. 2026. doi:10.21203/rs.3.rs-11053221/v1.
BibTeX
@article{frigon2026-6670fbf6,
author = {Frigon, E. and Metz, A. and Parent, O. and Chadwick, K. and Kamal, F. and Alasmar, Z. and Brzezinski-Rittner, A. and Moqadam, R. and others},
title = {{Underlying histopathology features of white matter hyperintensities in vascular and neurodegenerative disorders: a systematic review}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11053221/v1},
url = {https://doi.org/10.21203/rs.3.rs-11053221/v1}
}
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Key findings
- As a result, histopathological data on WMHs from gold-standard studies remain limited relative to their clinical prevalence.
- The findings overall suggest that WMHs are pathologically heterogeneous, varying according to their anatomical location and distribution.
Study details
- Participants45
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 27 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, effect reported and randomised / 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 multi-centre collaboration, so those were left out: it earned 17 of the 62 points we could judge it on, which is 27 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” 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 | 45 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) |
| Randomised / blinded | 0 / 2 | No randomisation 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 |
| Multi-centre 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 | 17 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 17 of the 62 points we could judge it on is 27 out of 100. |
| Total | 27 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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