Location-specific Longitudinal Patterns of Subcortical and Lobar Cerebral Microhemorrhages in Preclinical Alzheimer Disease
- 1University of Southampton School of Medicine: University of Southampton Faculty of Medicine
Abstract
Background and ObjectivesCerebral microhaemorrhages influence eligibility and monitoring for anti-amyloid therapies. Emerging evidence and expert opinion suggest that subcortical microhaemorrhages may be less closely related to cerebral amyloidosis than lobar lesions and may therefore warrant separate consideration in anti-amyloid treatment eligibility criteria. Using longitudinal MRI data from cognitively unimpaired individuals with preclinical Alzheimer disease in the A4 study, we hypothesised that lobar and subcortical microhaemorrhages would show distinct location-specific patterns of progression and associated risk profiles.
MethodsWe conducted a retrospective longitudinal cohort analysis of centrally assessed MRI data from A4 study participants with at least two evaluable MRI examinations. Baseline and follow-up were defined as the first and last evaluable scans, respectively. Participants were classified according to the anatomical distribution of baseline microhaemorrhages as lobar or subcortical, and subsequent location-specific lesion accumulation was examined. Multivariable logistic regression was used to assess whether baseline lobar and subcortical microhaemorrhage counts were independently associated with the development of additional lobar and subcortical microhaemorrhages.
ResultsAmong 1,146 participants followed for a mean of 4.55 years (SD = 1.78), 38 had subcortical-only and 157 had lobar-only microhaemorrhages at baseline. Subsequent lesions preferentially accumulated in the same anatomical compartment. Baseline subcortical microhaemorrhage count was associated with additional subcortical lesions (OR 3.60, 95% CI 2.00-6.47), but not with additional lobar lesions (OR 1.25, 95% CI 0.73-2.15). Conversely, baseline lobar microhaemorrhage count was associated with additional lobar lesions (OR 2.74, 95% CI 2.06-3.64), but not with additional subcortical lesions (OR 1.08, 95% CI 0.77-1.53). White matter hyperintensity burden was associated with subcortical progression, while APOE {varepsilon}4 homozygosity and greater cerebral amyloid burden were associated with lobar progression. Systolic blood pressure was directionally positive but not associated with lobar microhaemorrhage accumulation in either analysis.
DiscussionOur findings support the emerging view that subcortical and lobar microhaemorrhages exhibit distinct longitudinal patterns and associated risk profiles. Longitudinal studies in patients receiving contemporary plaque-clearing therapies are needed to determine whether microhaemorrhages should be considered differently according to anatomical location in treatment eligibility and monitoring guidelines.
Related
- Physical activity in preclinical Alzheimer disease: current evidence and implications for multimodal longitudinal research
- Global brain activity links subcortical degeneration to cortical tau progressively across Braak regions over early Alzheimer's disease stages.
- Dying in the Desired Location—Findings From the Canadian Longitudinal Study on Aging
- Olfactory Function in Preclinical Alzheimer's Disease: A Multi-Cohort Study
- Exploring healthy aging through preclinical Alzheimer disease in the Knight Alzheimer Research Imaging dataset
BibTeX
@misc{hill2026locationspecific,
title = {{Location-specific Longitudinal Patterns of Subcortical and Lobar Cerebral Microhemorrhages in Preclinical Alzheimer Disease}},
author = {C. Hill and S. Michopoulou and M. Niranjan and C. Kipps},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.12.26365339},
url = {https://www.medrxiv.org/content/10.64898/2026.10.12.26365339v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Location-specific Longitudinal Patterns of Subcortical and Lobar Cerebral Microhemorrhages in Preclinical Alzheimer Disease
AU - C. Hill
AU - S. Michopoulou
AU - M. Niranjan
AU - C. Kipps
PY - 2026
DA - 2026/10/12
PB - medRxiv
DO - 10.64898/2026.10.12.26365339
UR - https://www.medrxiv.org/content/10.64898/2026.10.12.26365339v1
AB - Background and ObjectivesCerebral microhaemorrhages influence eligibility and monitoring for anti-amyloid therapies. Emerging evidence and expert opinion suggest that subcortical microhaemorrhages may be less closely related to cerebral amyloidosis than lobar lesions and may therefore warrant separate consideration in anti-amyloid treatment eligibility criteria. Using longitudinal MRI data from cognitively unimpaired individuals with preclinical Alzheimer disease in the A4 study, we hypothesised that lobar and subcortical microhaemorrhages would show distinct location-specific patterns of progression and associated risk profiles. MethodsWe conducted a retrospective longitudinal cohort analysis of centrally assessed MRI data from A4 study participants with at least two evaluable MRI examinations. Baseline and follow-up were defined as the first and last evaluable scans, respectively. Participants were classified according to the anatomical distribution of baseline microhaemorrhages as lobar or subcortical, and subsequent location-specific lesion accumulation was examined. Multivariable logistic regression was used to assess whether baseline lobar and subcortical microhaemorrhage counts were independently associated with the development of additional lobar and subcortical microhaemorrhages. ResultsAmong 1,146 participants followed for a mean of 4.55 years (SD = 1.78), 38 had subcortical-only and 157 had lobar-only microhaemorrhages at baseline. Subsequent lesions preferentially accumulated in the same anatomical compartment. Baseline subcortical microhaemorrhage count was associated with additional subcortical lesions (OR 3.60, 95% CI 2.00-6.47), but not with additional lobar lesions (OR 1.25, 95% CI 0.73-2.15). Conversely, baseline lobar microhaemorrhage count was associated with additional lobar lesions (OR 2.74, 95% CI 2.06-3.64), but not with additional subcortical lesions (OR 1.08, 95% CI 0.77-1.53). White matter hyperintensity burden was associated with subcortical progression, while APOE {varepsilon}4 homozygosity and greater cerebral amyloid burden were associated with lobar progression. Systolic blood pressure was directionally positive but not associated with lobar microhaemorrhage accumulation in either analysis. DiscussionOur findings support the emerging view that subcortical and lobar microhaemorrhages exhibit distinct longitudinal patterns and associated risk profiles. Longitudinal studies in patients receiving contemporary plaque-clearing therapies are needed to determine whether microhaemorrhages should be considered differently according to anatomical location in treatment eligibility and monitoring guidelines.
ER -