Thyroid hormone (TH) is crucial during neurodevelopment, but high levels of TH have been linked to neurodegenerative disorders. No data on the association of thyroid function with brain imaging in the general population are available. We therefore investigated the association of thyroid-stimulating hormone and free thyroxine (FT4) with magnetic resonance imaging (MRI)-derived total intracranial volume, brain tissue volumes, and diffusion tensor imaging measures of white matter microstructure in 4683 dementia- and stroke-free participants (mean age 60.2, range 45.6–89.9 years). Higher FT4 levels were associated with larger total intracranial volumes (β = 6.73 mL, 95% confidence interval = 2.94–9.80). Higher FT4 levels were also associated with larger total brain and white matter volumes in younger individuals, but with smaller total brain and white matter volume in older individuals (p-interaction 0.02). There was a similar interaction by age for the association of FT4 with mean diffusivity on diffusion tensor imaging (p-interaction 0.026). These results are in line with differential effects of TH during neurodevelopmental and neurodegenerative processes and can improve the understanding of the role of thyroid function in neurodegenerative disorders.

Background and Purpose- Inflammation is involved in the pathogenesis of large artery atherosclerosis, ischemic stroke, and Alzheimer dementia. However, the role of inflammation in cerebral small vessel disease and neurodegeneration remains poorly understood. We hypothesize that CRP (C-reactive protein) is associated with brain structural changes and may interact with amyloid to produce vascular and degenerative damage. We examined the association of CRP levels with imaging markers of cerebral small vessel disease and neurodegeneration. Furthermore, we studied the association of CRP with plasma Aβ (amyloid-β) levels and their joint effects with imaging markers. Methods- We included 2814 persons (mean age, 56.9 years; 44.8% women) from the Rotterdam Study with complete data on CRP and 1.5 T brain magnetic resonance imaging scans. Aβ levels were measured in a subsample (n=736). Markers of cerebral small vessel disease included lacunes, white matter hyperintensities, microbleeds, and enlarged perivascular spaces. Neurodegeneration was assessed by smaller volumes of gray matter, white matter, and hippocampus. Plasma levels of Aβ1-38, Aβ1-40, and Aβ1-42 were assessed using ELISA. Results- Higher CRP levels were associated with larger white matter hyperintensities volume (β=0.07; 95% CI, 0.00-0.13), increasing lacunar (rate ratios, 1.61; 95% CI, 1.19-2.19), enlarged perivascular spaces (rate ratios, 1.01; 95% CI, 1.00-1.03), and deep/infratentorial microbleeds (rate ratios, 1.30; 95% CI, 1.00-1.69) counts. People with high CRP levels had small gray matter volume. We also found significant interaction between CRP and Aβ such that among persons in higher tertiles of Aβ1-42, a strong association was observed between CRP and lacunar ( P interaction, 0.004), enlarged perivascular spaces ( P interaction, 0.002), and microbleed counts ( P interaction, <0.001). Similarly, among persons in higher tertile of Aβ1-38, a strong association was observed between CRP and microbleed counts ( P interaction, 0.004). Conclusions- Higher CRP levels were associated with subclinical markers of cerebral small vessel disease and neurodegeneration. This effect was augmented by an interaction between CRP and Aβ levels. Future longitudinal studies focusing on joint effects of CRP and Aβ on progression of magnetic resonance imaging markers and cognitive decline are warranted.

Purpose: To investigate the association between N-terminal pro-Btype natriuretic peptide (NT-proBNP), which is a marker of heart disease, and markers of subclinical brain damage on magnetic resonance (MR) images in community-dwelling middle-aged and elderly subjects without dementia and without a clinical diagnosis of heart disease. Materials and Methods: This prospective population-based cohort study was approved by a medical ethics committee overseen by the national government, and all participants gave written informed consent. Serum levels of NT-proBNP were measured in 2397 participants without dementia or stroke (mean age, 56.6 years; age range, 45.7-87.3 years) and without clinical diagnosis of heart disease who were drawn from the population-based Rotterdam Study. All participants were examined with a 1.5-T MR imager. Multivariable linear and logistic regression analyses were used to investigate the association between NT-proBNP level and MR imaging markers of subclinical brain damage, including volumetric, focal, and microstructural markers. Results: A higher NT-proBNP level was associated with smaller total brain volume (mean difference in z score per standard deviation increase in NT-proBNP level, -0.021; 95% confidence interval [CI]: -0.034, -0.007; P = .003) and was predominantly driven by gray matter volume (mean difference in z score per standard deviation increase in NT-proBNP level, -0.037; 95% CI: -0.057, -0.017; P < .001). Higher NT-proBNP level was associated with larger white matter lesion volume (mean difference in z score per standard deviation increase in NT-proBNP level, 0.090; 95% CI: 0.051, 0.129; P < .001), with lower fractional anisotropy (mean difference in z score per standard deviation increase in NT-proBNP level, -0.048; 95% CI: -0.088, -0.008; P = .019) and higher mean diffusivity (mean difference in z score per standard deviation increase in NT-proBNP level, 0.054; 95% CI: 0.018, 0.091; P = .004) of normal-appearing white matter. Conclusion: In community-dwelling persons, higher serum NT-proBNP levels are associated with volumetric and microstructural MR imaging markers of subclinical brain damage.

Despite a substantial genetic component, efforts to identify common genetic variation underlying depression have largely been unsuccessful. In the current study we aimed to identify rare genetic variants that might have large effects on depression in the general population. Using high-coverage exome-sequencing, we studied the exonic variants in 1265 individuals from the Rotterdam study (RS), who were assessed for depressive symptoms. We identified a missense Asn396Ser mutation (rs77960347) in the endothelial lipase (LIPG) gene, occurring with an allele frequency of 1% in the general population, which was significantly associated with depressive symptoms (P-value=5.2 × 10 -08, β=7.2). Replication in three independent data sets (N=3612) confirmed the association of Asn396Ser (P-value=7.1 × 10 -03, β=2.55) with depressive symptoms. LIPG is predicted to have enzymatic function in steroid biosynthesis, cholesterol biosynthesis and thyroid hormone metabolic processes. The Asn396Ser variant is predicted to have a damaging effect on the function of LIPG. Within the discovery population, carriers also showed an increased burden of white matter lesions (P-value=3.3 × 1 -02) and a higher risk of Alzheimer's disease (odds ration=2.01; P-value=2.8 × 10 -02) compared with the non-carriers. Together, these findings implicate the Asn396Ser variant of LIPG in the pathogenesis of depressive symptoms in the general population.

Purpose: To investigate intraplaque hemorrhage (IPH) development and change over time. Materials and Methods: Institutional review board approval and written informed consent from all participants were obtained. From a population-based study on subclinical atherosclerosis, 40 participants with IPH at baseline magnetic resonance (MR) imaging (53 carotids with IPH) were randomly selected and were matched with 27 control subjects (53 carotids without IPH) to undergo a second MR examination (mean interval, 17 months 6 4 [standard deviation]) to assess IPH change. IPH volume change was evaluated by using both a visual rating scale and an automated volumetric segmentation tool. Cardiovascular risk factors for IPH volume change were investigated with linear regression analyses. Results: IPH remained present in 50 (94%) of the 53 carotids with IPH at baseline, and it developed in fve (7%) of the 40 carotids without IPH at baseline. Visual progression of IPH volume was present in 14 (26%) of the 53 carotids with IPH at baseline, and regression was present in 16 (30%). Mean quantitative change in IPH volume was 213.7 mm³ ± 62.6 per year of follow-up. Male sex (men vs women, 37.7 mm³; 95% confdence interval [CI]: 11.0, 64.4; P =.006), smoking (smokers vs nonsmokers, 45.2 mm³; 95% CI: 7.1, 83.4; P =.020), and hypertension (subjects with hypertension vs those without hypertension, 32.5 mm³; 95% CI: 7.7, 57.2; P =.010) were associated with IPH volume change. Conclusion: During 17 months of follow-up, both visual progression and regression of IPH volume occurs, whereas quantitatively IPH volume decreases. This suggests that IPH is a dynamic process with potential for either growth or resolution over time.

Background and aims In a large stroke-free population, we sought to identify cardiovascular risk factors and carotid plaque components associated with carotid plaque burden, lumen volume and stenosis. Methods The carotid arteries of 1562 stroke-free participants from The Rotterdam Study were imaged on a 1.5-Tesla MRI scanner. Inner and outer wall of the carotid arteries were automatically segmented and lumen volume (mm³), wall volume (outer wall–inner wall) and plaque burden (wall volume/outer wall volume) (%) were quantified. Plaque components were visually determined and luminal stenosis was assessed. We analyzed associations of cardiovascular risk factors and carotid plaque components with plaque burden and lumen volumes using regression analysis. Results We investigated 2821 carotid plaques and found that women had larger plaque burden (50.7 ± 7.8% vs. 49.2 ± 7.7%, p <0.0001) and smaller lumen volumes (933 ± 286 mm³ vs. 1078 ± 334 mm³, p <0.0001) than men. In women, age, HDL-cholesterol and systolic blood pressure, and in men, total cholesterol, non-HDL cholesterol and statin use were independently associated with higher plaque burden and lumen volume. Furthermore, smoking and diabetes were associated with lumen volume in men (respectively p = 0.04 and p = 0.002). Intraplaque hemorrhage (IPH) and lipid were related to a larger plaque burden (OR 1.30 [1.05–1.60] and OR 1.28[1.06–1.55]). Finally, within the highest quartile of plaque burden, IPH was strongly associated with luminal stenosis independent of age, sex, plaque burden and composition (Beta = 15.2; [11.8–18.6]). Conclusions Several cardiovascular risk factors and plaque components, in particular IPH, are associated with higher plaque burden. Carotid IPH is strongly associated with an increased luminal stenosis.

Objective: To investigate the association of cerebral white matter microstructural integrity with mortality. Methods: We included 4,294 individuals, free from stroke and dementia (mean age 63.6 years, 44% male) from the population-based Rotterdam Study (2006-2011). Diffusion-MRI was used to assess the microstructural integrity of the white matter, both globally and for specific white matter tracts. Fractional anisotropy and mean diffusivity were the measures used to quantify white matter integrity. All-cause mortality and cause-specific mortality was recorded with a median follow-up time of 5.4 and 4.6 years, respectively. Cox regression models, adjusted for age, sex, APOE ϵ4 allele carriership, cardiovascular risk factors, and macrostructural MRI changes, were used to estimate hazard ratios. Results: During the follow-up time, 216 participants (5.0%) died of all causes, 31 (0.7%) of cardiovascular causes, and 102 individuals (2.4%) died of noncardiovascular causes. Each SD decrease in fractional anisotropy and each SD increase in mean diffusivity was associated with a 1.37-fold (95% confidence interval: 1.20-1.57) and a 1.49-fold (95% confidence interval: 1.28-1.75) higher hazard of all-cause mortality, respectively. The associations were more prominent with cardiovascular mortality than with noncardiovascular mortality. In tract-specific analyses, we observed that association tracts were more prominently related to mortality. Conclusions: Our findings suggest that impairments in cerebral white matter, even at early stages, are not limited to adverse brain outcomes and they are related to mortality, especially from cardiovascular causes.