INTRODUCTIONWe aimed to investigate the association between white matter hyperintensity (WMH) shape and volume and the long-term dementia risk in community-dwelling older adults. METHODSThree... Show moreINTRODUCTIONWe aimed to investigate the association between white matter hyperintensity (WMH) shape and volume and the long-term dementia risk in community-dwelling older adults. METHODSThree thousand seventy-seven participants (mean age: 75.6 +/- 5.2 years) of the Age Gene/Environment Susceptibility (AGES)-Reykjavik study underwent baseline 1.5T brain magnetic resonance imaging and were followed up for dementia (mean follow-up: 9.9 +/- 2.6 years). RESULTSMore irregular shape of periventricular/confluent WMH (lower solidity (hazard ratio (95% confidence interval) 1.34 (1.17 to 1.52), p < .001) and convexity 1.38 (1.28 to 1.49), p < .001); higher concavity index 1.43 (1.32 to 1.54), p < .001) and fractal dimension 1.45 (1.32 to 1.58), p < .001)), higher total WMH volume (1.68 (1.54 to 1.87), p < .001), higher periventricular/confluent WMH volume (1.71 (1.55 to 1.89), p < .001), and higher deep WMH volume (1.17 (1.08 to 1.27), p < .001) were associated with an increased long-term dementia risk. DISCUSSIONWMH shape markers may in the future be useful in determining patient prognosis and may aid in patient selection for future preventive treatments in community-dwelling older adults. Show less
Background: Studies on the association of cerebrovascular risk factors to magnetic resonance imaging detected brain infarcts have been inconsistent, partly reflecting limits of assessment to... Show moreBackground: Studies on the association of cerebrovascular risk factors to magnetic resonance imaging detected brain infarcts have been inconsistent, partly reflecting limits of assessment to infarcts anywhere in the brain, as opposed to specific brain regions. We hypothesized that risk-factors may differ depending on where the infarct is located in subcortical-, cortical-, and cerebellar regions. Methods: Participants (n=2662, mean age 74.6 +/- 4.8) from the longitudinal population-based AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study underwent brain magnetic resonance imaging at baseline and on average 5.2 years later. We assessed the number and location of brain infarcts (prevalent versus incident). We estimated the risk-ratios of prevalent (PRR) and incident (IRR) infarcts by baseline cerebrovascular risk-factors using Poisson regression. Results: Thirty-one percent of the study participants had prevalent brain infarcts and 21% developed new infarcts over 5 years. Prevalent subcortical infarcts were associated with hypertension (PRR, 2.7 [95% CI, 1.1-6.8]), systolic blood pressure (PRR, 1.2 [95% CI, 1.1-1.4]), and diabetes (PRR, 2.8 [95% CI, 1.9-4.1]); incident subcortical infarcts were associated with systolic (IRR, 1.2 [95% CI, 1.0-1.4]) and diastolic (IRR, 1.3 [95% CI, 1.0-1.6]) blood pressure. Prevalent and incident cortical infarcts were associated with carotid plaques (PRR, 1.8 [95% CI, 1.3-2.5] and IRR, 1.9 [95% CI, 1.3-2.9], respectively), and atrial fibrillation was significantly associated with prevalent cortical infarcts (PRR, 1.8 [95% CI, 1.2-2.7]). Risk-factors for prevalent cerebellar infarcts included hypertension (PRR, 2.45 [95% CI, 1.5-4.0]), carotid plaques (PRR, 1.45 [95% CI, 1.2-1.8]), and migraine with aura (PRR, 1.6 [95% CI, 1.1-2.2]). Incident cerebellar infarcts were only associated with any migraine (IRR, 1.4 [95% CI, 1.0-2.0]). Conclusions: The risk for subcortical infarcts tends to increase with small vessel disease risk-factors such as hypertension and diabetes. Risk for cortical infarcts tends to increase with atherosclerotic/coronary processes and risk for cerebellar infarcts with a more mixed profile of factors. Assessment of risk-factors by location of asymptomatic infarcts found on magnetic resonance imaging may improve the ability to target and optimize preventive therapeutic approaches to prevent stroke. Show less
Cerebral hypoperfusion leads to adverse sequalae including dementia. Midlife higher blood pressure (BP) can lead to low cerebral blood flow (CBF), but older persons may need higher BP to maintain... Show moreCerebral hypoperfusion leads to adverse sequalae including dementia. Midlife higher blood pressure (BP) can lead to low cerebral blood flow (CBF), but older persons may need higher BP to maintain cerebral perfusion. We investigated the associations among late-life BP, CBF, and cognition. Data are from 2498 participants with a mean age of 79.8 (SD, 4.7) years of the second exam of the AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study. BP was measured, and phase-contrast (PC) magnetic resonance imaging was acquired to estimate total brain CBFPC. Cognitive outcomes included verbal and working memory, processing speed, mild cognitive impairment, and all-cause dementia. Relationships among late-life BP, CBFPC, and cognition were assessed with regression models, controlling for socio-demographics, BP level at midlife (at a mean age of 49.6 [SD, 5.9] years), cardiovascular factors, and total brain volume. In fully adjusted models, each mm Hg increase in late-life diastolic BP was associated with a -0.082 mL/min per 100 mL (95% CI -0.123 to -0.041) lower CBFPC. In contrast, each mm Hg increase in late-life systolic BP or pulse pressure was associated with a 0.027 mL/min per 100 mL (95% CI, 0.0065-0.048) and 0.061 mL/min per 100 mL (95% CI, 0.038-0.084) higher late-life CBFPC, respectively. Higher CBFPC was significantly related to higher cognitive scores for psychomotor speed, verbal, and working memory and to a lower odd of mild cognitive impairment or dementia, irrespective of late-life BP level. Higher late-life diastolic BP and systolic BP were differentially associated with CBFPC. Our findings suggest CBF is an important correlate of late-life cognition, independent of BP level. Show less
Excessive pressure and flow pulsatility in first-generation branch arteries are associated with microvascular damage in high-flow organs like brain and kidneys. However, the contribution of local... Show moreExcessive pressure and flow pulsatility in first-generation branch arteries are associated with microvascular damage in high-flow organs like brain and kidneys. However, the contribution of local wave reflection and rereflection to microvascular damage remains controversial. Aortic flow, carotid pressure, flow and hydraulic power, brain magnetic resonance images, and cognitive scores were assessed in AGES-Reykjavik study participants without history of stroke, transient ischemic attack, or dementia (N=668, 378 women, 69-93 years of age). The aorta-carotid interface was generalized as a markedly asymmetrical bifurcation, with a large parent vessel (proximal aorta) branching into small (carotid) and large (distal aorta) daughter vessels. Local reflection coefficients were computed from aortic and carotid characteristic impedances. The bifurcation reflection coefficient, which determines pressure amplification in both daughter vessels, was low (0.06 +/- 0.03). The carotid flow transmission coefficient was low (0.11 +/- 0.04) and associated with markedly lower carotid versus aortic flow pulsatility (waveform SD, 7.2 +/- 2.0 versus 98.7 +/- 21.8 mL/s, P<0.001), pulsatility index (1.8 +/- 0.5 versus 4.5 +/- 0.6, P<0.001), and pulsatile power percentage (10 +/- 4% versus 25 +/- 5%, P<0.001). Transmitted as compared to incident pulsatile power (19.0 +/- 9.8 versus 35.9 +/- 17.8 mW, P<0.001) was further reduced by reflection (-4.3 +/- 2.7 mW) and rereflection (-12.5 +/- 8.1 mW) within the carotid. Higher carotid flow pulsatility correlated with lower white matter volume (R=-0.130, P<0.001) and lower memory scores (R=-0.161, P<0.001). Marked asymmetry of characteristic impedances at aorta-branch artery bifurcations limits amplification of pressure, markedly reduces absolute and relative pulsatility of transmitted flow and hydraulic power into first-generation branch arteries, and thereby protects the downstream local microcirculation from pulsatile damage. Show less
Sargurupremraj, M.; Suzuki, H.; Jian, X.Q.; Sarnowski, C.; Evans, T.E.; Bis, J.C.; ... ; Int Headache Genomics Consortium I 2020
White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide... Show moreWhite matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p=2.5x10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials. White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting. Show less
