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Association of Data-Driven White Matter Hyperintensity Spatial Signatures With Distinct Cerebral Small Vessel Disease Etiologies
Phuah CL, Chen Y, Strain JF, Yechoor N, Laurido-Soto OJ, Ances BM, Lee JM, Alzheimer's Disease Neuroimaging Initiative.. Neurology, 2022-12-05
Topic: Brain proteins, microglia and lab models
Background and objectives Topographical distribution of white matter hyperintensities (WMH) are hypothesized to vary by cerebrovascular risk factors. We used an unbiased pattern discovery approach to identify distinct WMH spatial patterns and investigate their association with different WMH etiologies. Methods We performed a cross-sectional study on participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) to identify spatially distinct WMH distribution patterns using voxel-based spectral clustering analysis of aligned WMH probability maps. We included all participants from the ADNI Grand Opportunity/ADNI 2 study with available baseline 2D-FLAIR MRI scans, without history of stroke or presence of infarction on imaging. We evaluated the associations of these WMH spatial patterns with vascular risk factors, amyloid-β PET, and imaging biomarkers of cerebral amyloid angiopathy (CAA), characterizing different forms of cerebral small vessel disease (CSVD) using multivariable regression. We also used linear regression models to investigate whether WMH spatial distribution influenced cognitive impairment. Results We analyzed MRI scans of 1,046 ADNI participants with mixed vascular and amyloid-related risk factors (mean age 72.9, 47.7% female, 31.4% hypertensive, 48.3% with abnormal amyloid PET). We observed unbiased partitioning of WMH into 5 unique spatial patterns: deep frontal, periventricular, juxtacortical, parietal, and posterior. Juxtacortical WMH were independently associated with probable CAA, deep frontal WMH were associated with risk factors for arteriolosclerosis (hypertension and diabetes), and parietal WMH were associated with brain amyloid accumulation, consistent with an Alzheimer disease (AD) phenotype. Juxtacortical, deep frontal, and parietal WMH spatial patterns were associated with cognitive impairment. Periventricular and posterior WMH spatial patterns were unrelated to any disease phenotype or cognitive decline. Discussion Data-driven WMH spatial patterns reflect discrete underlying etiologies including arteriolosclerosis, CAA, AD, and normal aging. Global measures of WMH volume may miss important spatial distinctions. WMH spatial signatures may serve as etiology-specific imaging markers, helping to resolve WMH heterogeneity, identify the dominant underlying pathologic process, and improve prediction of clinical-relevant trajectories that influence cognitive decline.
Key findings
- Results We analyzed MRI scans of 1,046 ADNI participants with mixed vascular and amyloid-related risk factors (mean age 72.9, 47.7% female, 31.4% hypertensive, 48.3% with abnormal amyloid PET).
- We observed unbiased partitioning of WMH into 5 unique spatial patterns: deep frontal, periventricular, juxtacortical, parietal, and posterior.
- Juxtacortical WMH were independently associated with probable CAA, deep frontal WMH were associated with risk factors for arteriolosclerosis (hypertension and diabetes), and parietal WMH were associated with brain amyloid accumulation, consistent with an Alzheimer disease (AD) phenotype.
- Juxtacortical, deep frontal, and parietal WMH spatial patterns were associated with cognitive impairment.
Why it matters
This cross-sectional study found that white matter hyperintensities in different brain locations were linked to different causes of small vessel disease, such as probable cerebral amyloid angiopathy for juxtacortical patterns and arteriolosclerosis risk factors for deep frontal patterns. It does not test any treatment, cure or prevention, so it offers no direct guidance for managing Alzheimer's disease.
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Study details
- Study designcross-sectional
- Effect size47.7%; 31.4%; 48.3%
- Evidence strengthLow
How this study scored 58/100
Published in a leading specialty journal, and it is a snapshot of people at one point in time. Scored zero for sample size, studied in people and randomised / blinded because the record does not state it. We have no data on senior author's track record, so that was left out: it earned 56 of the 96 points we could judge it on, which is 58 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Neurology) |
| Journal's citation record | 4 / 4 | Neurology: journal h-index 525 (OpenAlex, 2026-10-29) |
| Study design | 4 / 12 | A snapshot of people at one point in time |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2022 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 2 / 3 | Effect reported as a number, without an interval or test |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 4 / 7 | Cited 99 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 16.5 citations a year over 6 year(s) since 2022 |
| Impact for its field and year | 4 / 6 | Cited 9.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 8 other studies in this library |
| Still being cited | 3 / 4 | Cited 76 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | 2 / 3 | Washington University in St. Louis: institution h-index 1,962 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 36123127) |
| Free to read | 2 / 2 | Free to read |
| Points | 56 / 96 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 56 of the 96 points we could judge it on is 58 out of 100. |
| Total | 58 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1212/wnl.0000000000201186
- PubMed: 36123127
- Original source →
- Free full text: PubMed Central →
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 8 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Phuah, C. L., Chen, Y., Strain, J. F., Yechoor, N., Laurido-Soto, O. J., Ances, B. M., et al. (2022). Association of Data-Driven White Matter Hyperintensity Spatial Signatures With Distinct Cerebral Small Vessel Disease Etiologies. Neurology. https://doi.org/10.1212/wnl.0000000000201186
Vancouver
Phuah CL, Chen Y, Strain JF, Yechoor N, Laurido-Soto OJ, Ances BM, et al. Association of Data-Driven White Matter Hyperintensity Spatial Signatures With Distinct Cerebral Small Vessel Disease Etiologies. Neurology. 2022. doi:10.1212/wnl.0000000000201186. PMID: 36123127.
BibTeX
@article{phuah2022-36123127,
author = {Phuah, C. L. and Chen, Y. and Strain, J. F. and Yechoor, N. and Laurido-Soto, O. J. and Ances, B. M. and Lee, J. M. and {Alzheimer's Disease Neuroimaging Initiative}},
title = {{Association of Data-Driven White Matter Hyperintensity Spatial Signatures With Distinct Cerebral Small Vessel Disease Etiologies}},
journal = {Neurology},
year = {2022},
doi = {10.1212/wnl.0000000000201186},
pmid = {36123127},
url = {https://doi.org/10.1212/wnl.0000000000201186}
}
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