White Matter Regions With Low Microstructure in Young Adults Spatially Coincide With White Matter Hyperintensities in Older Adults

Lao, Patrick J.; Vorburger, Robert S.; Narkhede, Atul; Gazes, Yunglin; Igwe, Kay C.; Colón, Juliet M.; Amarante, Erica; Guzman, Vanessa A.; Habeck, Christian; Stern, Yaakov; Brickman, Adam M.

doi:10.3389/fnagi.2019.00345

Cited by 3 publications

(3 citation statements)

References 47 publications

(62 reference statements)

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“…The increase in WMH with age is well documented in the general population (95-96% of those aged >60 years 45,46 and 100% of those aged >65 years 47 in the general population). In these adults with DS, 100% had detectable WMH (range = 0.01-23.0cm 3 ).…”

Section: Discussionmentioning

confidence: 91%

Alzheimer‐Related Cerebrovascular Disease in Down Syndrome

Lao

Gutierrez

Keator

et al. 2020

Annals of Neurology

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Objective: Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross-sectional relationship with age, beta-amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status. Methods: Participants from the Biomarkers of Alzheimer's Disease in Down Syndrome study (n = 138, 50 ± 7 years, 39% women) with MRI data and a subset (n = 90) with amyloid positron emission tomography (PET) were included. We derived MRI-based biomarkers of cerebrovascular pathology, including white matter hyperintensities (WMH), infarcts, cerebral microbleeds, and enlarged perivascular spaces (PVS), as well as PET-based biomarkers of amyloid burden. Participants were characterized as cognitively stable (CS), mild cognitive impairment-DS (MCI-DS), possible AD dementia, or definite AD dementia based on in-depth assessments of cognition, function, and health status. Results: There were detectable WMH, enlarged PVS, infarcts, and microbleeds as early as the 5th decade of life. There was a monotonic increase in WMH volume, enlarged PVS, and presence of infarcts across diagnostic groups (CS < MCI-DS < possible AD dementia < definite AD dementia). Higher amyloid burden was associated with a higher likelihood of an infarct. Interpretation: The findings highlight the prevalence of cerebrovascular disease in adults with DS and add to a growing body of evidence that implicates cerebrovascular disease as a core feature of AD and not simply a comorbidity.

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Section: Discussionmentioning

confidence: 91%

Alzheimer‐Related Cerebrovascular Disease in Down Syndrome

Lao

Gutierrez

Keator

et al. 2020

Annals of Neurology

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“…Our results support a robust relation between genetic determinants of WMH, the most common imaging feature of cSVD in older adults, and NODDI markers, especially NDI, in young adults. Interestingly, associations of genetically predicted WMH with NDI markers at age 20 were observed primarily in white matter regions most commonly affected by WMH in older age [90,91], such as the anterior, posterior and superior corona radiata, posterior thalamic radiation, and superior longitudinal fasciculus. This corroborates recent observations that areas where WMH are most likely to appear in older adults are also those with the lowest white matter microstructure integrity on DTI in young adults [91].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, associations of genetically predicted WMH with NDI markers at age 20 were observed primarily in white matter regions most commonly affected by WMH in older age [90,91], such as the anterior, posterior and superior corona radiata, posterior thalamic radiation, and superior longitudinal fasciculus. This corroborates recent observations that areas where WMH are most likely to appear in older adults are also those with the lowest white matter microstructure integrity on DTI in young adults [91]. In contrast, we found no association of genetically determined blood pressure, the main known risk factor for WMH, with NDI, suggesting that the association between genetically predicted WMH and NDI was likely not mediated by blood pressure.…”

Section: Discussionmentioning

confidence: 99%

Diffusion imaging genomics provides novel insight into early mechanisms of cerebral small vessel disease

Le Grand,

Tsuchida,

Koch

et al. 2024

Mol Psychiatry

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Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Genetic risk loci for white matter hyperintensities (WMH), the most common MRI-marker of cSVD in older age, were recently shown to be significantly associated with white matter (WM) microstructure on diffusion tensor imaging (signal-based) in young adults. To provide new insights into these early changes in WM microstructure and their relation with cSVD, we sought to explore the genetic underpinnings of cutting-edge tissue-based diffusion imaging markers across the adult lifespan. We conducted a genome-wide association study of neurite orientation dispersion and density imaging (NODDI) markers in young adults (i-Share study: N = 1 758, (mean[range]) 22.1[18–35] years), with follow-up in young middle-aged (Rhineland Study: N = 714, 35.2[30–40] years) and late middle-aged to older individuals (UK Biobank: N = 33 224, 64.3[45–82] years). We identified 21 loci associated with NODDI markers across brain regions in young adults. The most robust association, replicated in both follow-up cohorts, was with Neurite Density Index (NDI) at chr5q14.3, a known WMH locus in VCAN. Two additional loci were replicated in UK Biobank, at chr17q21.2 with NDI, and chr19q13.12 with Orientation Dispersion Index (ODI). Transcriptome-wide association studies showed associations of STAT3 expression in arterial and adipose tissue (chr17q21.2) with NDI, and of several genes at chr19q13.12 with ODI. Genetic susceptibility to larger WMH volume, but not to vascular risk factors, was significantly associated with decreased NDI in young adults, especially in regions known to harbor WMH in older age. Individually, seven of 25 known WMH risk loci were associated with NDI in young adults. In conclusion, we identified multiple novel genetic risk loci associated with NODDI markers, particularly NDI, in early adulthood. These point to possible early-life mechanisms underlying cSVD and to processes involving remyelination, neurodevelopment and neurodegeneration, with a potential for novel approaches to prevention.

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