Carola Mayer

BACKGROUND: White matter hyperintensities (WMHs) of presumed vascular origin are common in the elderly and are associated with vascular risk factors. There is evidence that vascular risk factors, in particular hypertension, are associated with WMH in particular locations of the white matter. However, it remains unclear whether this is true for all risk factors and whether signature WMH locations differ between risk factors. We aimed to identify WMH locations associated with vascular risk factors in community-dwelling individuals. METHODS: We pooled cross-sectional data from 16 population-based cohorts (15 653 individuals; mean age, 64.2±11.8 years; 52.2% female) through the Meta VCI Map Consortium. We quantified associations between WMH volumes in 50 white matter regions and 6 vascular risk factors using linear mixed models. Analyses were corrected for age, sex, study site, and total WMH volume. RESULTS: Hypertension (B=0.141; P P P P =0.034) were significantly associated with higher total WMH volume, whereas obesity (B=0.023; P =0.139) and hypercholesterolemia (B=0.009; P =0.531) were not. After correcting for total WMH volume, hypertension was associated with WMH volume in 10 regions (ie, bilateral external capsule, superior longitudinal fasciculus, superior corona radiata, anterior limb of the internal capsule, left anterior corona radiata, and left superior fronto-occipital fasciculus), smoking (body corpus callosum), diabetes (genu corpus callosum), and obesity (left inferior fronto-occipital fasciculus), each with one region. CONCLUSIONS: Hypertension has a signature WMH pattern, whereas associations between other vascular risk factors and regional WMH volumes seem to be mainly explained by a global increase in WMH rather than region-specific effects.

The link between metabolic syndrome (MetS) and neurodegenerative as well as cerebrovascular conditions holds substantial implications for brain health in at-risk populations. This study elucidates the complex relationship between MetS and brain health by conducting a comprehensive examination of cardiometabolic risk factors, brain morphology, and cognitive function in 40,087 individuals. Multivariate, data-driven statistics identified a latent dimension linking more severe MetS to widespread brain morphological abnormalities, accounting for up to 71% of shared variance in the data. This dimension was replicable across sub-samples. In a mediation analysis, we could demonstrate that MetS-related brain morphological abnormalities mediated the link between MetS severity and cognitive performance in multiple domains. Employing imaging transcriptomics and connectomics, our results also suggest that MetS-related morphological abnormalities are linked to the regional cellular composition and macroscopic brain network organization. By leveraging extensive, multi-domain data combined with a dimensional stratification approach, our analysis provides profound insights into the association of MetS and brain health. These findings can inform effective therapeutic and risk mitigation strategies aimed at maintaining brain integrity.

The association of shift work (SW) and disrupted circadian rhythm with markers of large artery atherosclerosis and cerebral small vessel disease is uncertain. We aimed to study the separate association of current and former SW with these markers. We included participants from the population-based Hamburg City Health Study. SW was defined by monthly working hours between 06:00 pm and 07:00 am containing night shifts for at least 12 months. Cross-sectional data were obtained from structured questionnaires, laboratory analyses, physical examinations, brain magnetic resonance imaging, and carotid ultrasound. We performed multivariable regression analysis with carotid intima-media thickness (CIMT), and peak-width skeletonized mean diffusivity (PSMD) as dependent variables. Three hundred and forty-four current, 238 former, and 7162 never-shift workers were included. The median age was 60 years for both current and former shift workers, and total duration of SW was comparable for the two groups. Current shift workers were less frequently female (27.3% vs. 44.5%; p < .001), had more frequent hyperlipidemia (31.5% vs. 22.3%; p = .024), and diabetes (16.2% vs. 3.2%; p < .001). After adjustment for age and sex, reduced quality of sleep (β = 1.61, p = .001) and low education (β = 2.63, p < .001) were associated with current but not former SW. Adjusted for age and sex, the current SW was associated with higher CIMT (β = 0.02, p = .001) and PSMD (β = 9.06e-06, p = .006), whereas former SW was not. Adjusted for risk factors, current SW remained associated with PSMD (β = 9.91e-06, p = .006) but not with CIMT. Current SW was associated with CIMT and with PSMD, with the latter association remaining after adjustment for risk factors. Former SW showed no associations with CIMT or PSMD. This may indicate that current SW is linked with increased neurovascular risk through disrupted circadian rhythms. The trial was submitted at http://www.clinicaltrials.gov, under NCT03934957 on January 4, 2019. The first participant was enrolled in February 2016.

Aim: The aim of the PAROBRAIN study was to examine the association of periodontal health with microstructural white matter integrity and cerebral small vessel disease (CSVD) in the Hamburg City Health Study, a large population‐based cohort with dental examination and brain magnetic resonance imaging (MRI).Materials and Methods: Periodontal health was determined by measuring clinical attachment loss (CAL) and plaque index. Additionally, the decayed/missing/filled teeth (DMFT) index was quantified. 3D‐FLAIR and 3D‐T1‐weighted images were used for white matter hyperintensity (WMH) segmentation. Diffusion‐weighted MRI was used to quantify peak width of skeletonized mean diffusivity (PSMD).Results: Data from 2030 participants were included in the analysis. Median age was 65 years, with 43% female participants. After adjusting for age and sex, an increase in WMH load was significantly associated with more CAL, higher plaque index and higher DMFT index. PSMD was significantly associated with the plaque index and DMFT. Additional adjustment for education and cardiovascular risk factors revealed a significant association of PSMD with plaque index (p < .001) and DMFT (p < .01), whereas effects of WMH load were attenuated (p > .05).Conclusions: These findings suggest an adverse effect of periodontal health on CSVD and white matter integrity. Further research is necessary to examine whether early treatment of periodontal disease can prevent microstructural brain damage.

Despite associations of regular coffee consumption with fewer neurodegenerative disorders, its association with microstructural brain alterations is unclear. To address this, we examined the association of coffee consumption with brain MRI parameters representing vascular brain damage, neurodegeneration, and microstructural integrity in 2316 participants in the population-based Hamburg City Health Study. Cortical thickness and white matter hyperintensity (WMH) load were measured on FLAIR and T1-weighted images. Microstructural white matter integrity was quantified as peak width of skeletonized mean diffusivity (PSMD) on diffusion-weighted MRI. Daily coffee consumption was assessed in five groups (6 cups). In multiple linear regressions, we examined the association between brain MRI parameters and coffee consumption (reference group p = 0.028) and higher cortical thickness (p = 0.015) compared to 0.05). The findings indicate that regular coffee consumption is positively associated with microstructural white matter integrity and cortical thickness. Further research is necessary to determine longitudinal effects of coffee on brain microstructure.

Age-related cortical atrophy, approximated by cortical thickness measurements from magnetic resonance imaging, follows a characteristic pattern over the lifespan. Although its determinants remain unknown, mounting evidence demonstrates correspondence between the connectivity profiles of structural and functional brain networks and cortical atrophy in health and neurological disease. Here, we performed a cross-sectional multimodal neuroimaging analysis of 2633 individuals from a large population-based cohort to characterize the association between age-related differences in cortical thickness and functional as well as structural brain network topology. We identified a widespread pattern of age-related cortical thickness differences including “hotspots” of strong age effects located in brain areas with high centrality (structural network hubs). Regional age-related differences were furthermore strongly correlated within the structurally defined node neighborhood. The overall pattern of thickness differences as well as its change throughout the later lifespan was found to be anchored in the functional network hierarchy as encoded by macroscale functional connectivity gradients. Lastly, the identified difference pattern covaried significantly with cognitive and motor performance. Our findings indicate that connectivity profiles of functional and structural brain networks might act as organizing principles behind age-related cortical thinning as an imaging surrogate of cortical atrophy.

As SARS-CoV-2 infections have been shown to affect the central nervous system, the investigation of associated alterations of brain structure and neuropsychological sequelae is crucial to help address future health care needs. Therefore, we performed a comprehensive neuroimaging and neuropsychological assessment of 223 non-vaccinated individuals recovered from a mild to moderate SARS-CoV-2 infection (100 female/123 male, age [years], mean ± SD, 55.54 ± 7.07; median 9.7 months after infection) in comparison with 223 matched controls (93 female/130 male, 55.74 ± 6.60) within the framework of the Hamburg City Health Study. Primary study outcomes were advanced diffusion magnetic resonance imaging (MRI) measures of white matter microstructure, cortical thickness, white matter hyperintensity load and neuropsychological test scores. Among all 11 MRI markers tested, significant differences were found in global measures of mean diffusivity and extracellular free-water which were elevated in the white matter of post-SARS-CoV-2 individuals comparing to matched controls (free-water: 0.148 ± 0.018 vs. 0.142 ± 0.017, P <.001; mean diffusivity [10 ⁻³ mm ² /s]: 0.747 ± 0.021 vs. 0.740 ± 0.020, P <.001). Group classification accuracy based on diffusion imaging markers was up to 80%. Neuropsychological test scores did not significantly differ between groups. Collectively, our findings suggest that subtle changes in white matter extracellular water content last beyond the acute infection with SARS-CoV-2. However, in our sample, a mild to moderate SARS-CoV-2 infection was not associated with neuropsychological deficits, significant changes in cortical structure or vascular lesions several months after recovery. External validation of our findings and longitudinal follow-up investigations are needed. Significance statement: In this case-control study, we demonstrate that non-vaccinated individuals recovered from a mild to moderate SARS-CoV-2 infection show significant alterations of the cerebral white matter identified by diffusion weighted imaging, such as global increases in extracellular free-water and mean diffusivity. Despite the observed brain white matter alterations in this sample, a mild to moderate SARS-CoV-2 infection was not associated with worse cognitive functions within the first year after recovery. Collectively, our findings indicate the presence of a prolonged neuroinflammatory response to the initial viral infection. Further longitudinal research is necessary to elucidate the link between brain alterations and clinical features of post-SARS-CoV-2 individuals.

In cerebral small vessel disease (CSVD), both white matter hyperintensities (WMH) of presumed vascular origin and the normal-appearing white matter (NAWM) contain microstructural brain alterations on diffusion-weighted MRI (DWI). Contamination of DWI-derived metrics by extracellular free-water can be corrected with free-water (FW) imaging. We investigated the alterations in FW and FW-corrected fractional anisotropy (FA-t) in WMH and surrounding tissue and their association with cerebrovascular risk factors. We analysed 1,000 MRI datasets from the Hamburg City Health Study. DWI was used to generate FW and FA-t maps. WMH masks were segmented on FLAIR and T1-weighted MRI and dilated repeatedly to create 8 NAWM masks representing increasing distance from WMH. Linear models were applied to compare FW and FA-t across WMH and NAWM masks and in association with cerebrovascular risk. Median age was 64 ± 14 years. FW and FA-t were altered 8 mm and 12 mm beyond WMH, respectively. Smoking was significantly associated with FW in NAWM (p = 0.008) and FA-t in WMH (p = 0.008) and in NAWM (p = 0.003) while diabetes and hypertension were not. Further research is necessary to examine whether FW and FA-t alterations in NAWM are predictors for developing WMH.

Long-term sequelae may occur after SARS-CoV-2 infection. We comprehensively assessed organ-specific functions in individuals after mild to moderate SARS-CoV-2 infection compared with controls from the general population. Four hundred and forty-three mainly non-hospitalized individuals were examined in median 9.6 months after the first positive SARS-CoV-2 test and matched for age, sex, and education with 1328 controls from a population-based German cohort. We assessed pulmonary, cardiac, vascular, renal, and neurological status, as well as patient-related outcomes. Bodyplethysmography documented mildly lower total lung volume (regression coefficient −3.24, adjusted P = 0.014) and higher specific airway resistance (regression coefficient 8.11, adjusted P = 0.001) after SARS-CoV-2 infection. Cardiac assessment revealed slightly lower measures of left (regression coefficient for left ventricular ejection fraction on transthoracic echocardiography −0.93, adjusted P = 0.015) and right ventricular function and higher concentrations of cardiac biomarkers (factor 1.14 for high-sensitivity troponin, 1.41 for N-terminal pro-B-type natriuretic peptide, adjusted P ≤ 0.01) in post-SARS-CoV-2 patients compared with matched controls, but no significant differences in cardiac magnetic resonance imaging findings. Sonographically non-compressible femoral veins, suggesting deep vein thrombosis, were substantially more frequent after SARS-CoV-2 infection (odds ratio 2.68, adjusted P < 0.001). Glomerular filtration rate (regression coefficient −2.35, adjusted P = 0.019) was lower in post-SARS-CoV-2 cases. Relative brain volume, prevalence of cerebral microbleeds, and infarct residuals were similar, while the mean cortical thickness was higher in post-SARS-CoV-2 cases. Cognitive function was not impaired. Similarly, patient-related outcomes did not differ. Subjects who apparently recovered from mild to moderate SARS-CoV-2 infection show signs of subclinical multi-organ affection related to pulmonary, cardiac, thrombotic, and renal function without signs of structural brain damage, neurocognitive, or quality-of-life impairment. Respective screening may guide further patient management. The key question is: How does a mild to moderate course of SARS-CoV-2 infection in mainly non-hospitalized individuals impact intermediate-term organ-specific functions in comparison to the general population? The key findings are (i) a mild to moderate course of SARS-CoV-2 infection is associated with subsequent signs of subclinical multi-organ affection; (ii) associations mainly affect the pulmonary, cardiac, coagulation, and renal system; and (iii) no systematic associations with structural brain damage, neurocognition, or quality of life were observed. The take-home message is systematic screening of multi-organ function even after mild to moderate SARS-CoV-2 infection is recommended to identify individuals at risk and initiate appropriate preventive therapies.