Biology subjects

Kukull, W.

Publications and source records attributed to Kukull, W..

3 recordsLinked to original sources

bioRxiv2026

Topographic reference modelling of white matter hyperintensities across the adult lifespan

White matter hyperintensities (WMH) are among the most common MRI findings in older adults. They are widely regarded as markers of brain aging and cerebral small-vessel disease, and associated with risk for cognitive decline, Alzheimers disease and related dementias (ADRD), and stroke. White matter hyperintensities (WMH) are typically interpreted by total lesion burden, but lesions with similar volumes can occupy different anatomical locations, potentially reflecting distinct pathological processes. Here we present voxelwise topographic reference modelling (vTRM), a framework for characterizing individual WMH masks against age- and sex-stratified frequency maps derived from cognitively unimpaired individuals. Using 42,469 FLAIR-derived lesion masks from twelve adult cohorts, we mapped population-level WMH spatial vulnerability, characterized age-related changes in its distribution across periventricular, lobar and arterial-territory compartments, and constructed paired percentile charts for lesion burden and spatial typicality. A quadrant-based classification defined by these two percentile dimensions revealed graded relationships with ADRD pathophysiology, neurodegeneration, and cognitive impairment, while identifying WMH patterns differentially associated with ageing-related, vascular and neurodegenerative processes among individuals with similar lesion volumes. These reference charts establish a benchmark for normative WMH ageing, enabling quantification of individual deviations from typical age-, sex- and burden-related patterns and identification of WMH phenotypes associated with vascular, neurodegenerative or mixed etiologies. The framework, together with a deployable 3D U-Net model trained on these data for automated WMH segmentation, is available through the Brain Lesion Analytics platform (https://brainlesionanalytics.org/).

neuroscience↗

bioRxiv2024

Sex, racial, and APOE-ϵ4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSThe effects of sex, race, and Apolipoprotein E (APOE) - Alzheimers disease (AD) risk factors - on white matter integrity are not well characterized. METHODSDiffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 {+/-} 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-{varepsilon}4 carrier status. RESULTSSex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr in projection tracts, and APOE-{varepsilon}4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSIONThere are prominent differences in white matter microstructure by sex, race, and APOE- {varepsilon}4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted. HighlightsO_LISex, race, and APOE-{varepsilon}4 carrier status relate to white matter microstructural integrity C_LIO_LIFemales generally have lower FAFWcorr compared to males C_LIO_LINon-Hispanic Black adults generally have lower FAFWcorr than non-Hispanic White adults C_LIO_LIAPOE-{varepsilon}4 carriers tended to have higher FW than non-carriers C_LI Research in Context Systematic ReviewThe authors used PubMed and Google Scholar to review literature that used conventional and free-water (FW)-corrected microstructural metrics to evaluate sex, race, and APOE-{varepsilon}4 differences in white matter microstructure. While studies have previously explored differences by sex and APOE-{varepsilon}4 status, less is known about racial differences and no large-scale FW-corrected analysis has been performed. InterpretationSex and race were more associated with FAFWcorr while APOE-{varepsilon}4 status was associated with FW metrics. Association, projection, limbic, and occipital transcallosal tracts showed the greatest differences. Future DirectionFuture studies to determine the biological and social pathways that lead to sex, racial, and APOE-{varepsilon}4 differences are warranted. Consent StatementAll participants provided informed consent in their respective cohort studies.

neuroscience↗

bioRxiv2019

Sex-dependent polygenic effects on the clinical progressions of Alzheimer’s disease

Sex differences in the manifestations of Alzheimers disease (AD) are under intense investigations 1,2. Despite the emerging importance of polygenic predictions for AD 3-8, the sex-dependent polygenic effects have not been demonstrated. Here, using a sex crossover analysis, we show that sex-dependent autosomal genetic effects on AD can be revealed by characterizing disease progress via the hazard function. We first performed sex-stratified genome-wide associations, and then applied derived sex-dependent weights to two independent cohorts. Sex-matched polygenic hazard scores (PHS) have significantly stronger associations with age-at-disease-onset, clinical progressions, amyloid depositions, neurofibrillary tangles, and composite neuropathological scores, than sex-mismatched PHS, independent of apolipoprotein E. Models without using hazard weights, i.e. polygenic risk scores (PRS), have lower predictive power than PHS and show no evidence for sex differences. Our results indicate revealing sex-dependent genetic architecture requires the consideration of temporal processes of AD. This has strong implications not only for the genetic underpinning of AD but also for how we estimate sex-dependent polygenic effects for clinical use.

genetics↗