Individual characteristics outperform resting-state fMRI for the prediction of behavioral phenotypes.

In this study, we aimed to compare imaging-based features of brain function, measured by resting-state fMRI (rsfMRI), with individual characteristics such as age, gender, and total intracranial volume to predict behavioral measures. We developed a machine learning framework based on rsfMRI features in a dataset of 20,000 healthy individuals from the UK Biobank, focusing on temporal complexity and functional connectivity measures. Our analysis across four behavioral phenotypes revealed that both temporal complexity and functional connectivity measures provide comparable predictive performance. However, individual characteristics consistently outperformed rsfMRI features in predictive accuracy, particularly in analyses involving smaller sample sizes. Integrating rsfMRI features with demographic data sometimes enhanced predictive outcomes. The efficacy of different predictive modeling techniques and the choice of brain parcellation atlas were also examined, showing no significant influence on the results. To summarize, while individual characteristics are superior to rsfMRI in predicting behavioral phenotypes, rsfMRI still conveys additional predictive value in the context of machine learning, such as investigating the role of specific brain regions in behavioral phenotypes.

Mapping the interplay of atrial fibrillation, brain structure, and cognitive dysfunction.

INTRODUCTION: Atrial fibrillation (AF) is associated with an elevated risk of cognitive impairment and dementia. Understanding the cognitive sequelae and brain structural changes associated with AF is vital for addressing ensuing health care needs. METHODS AND RESULTS: We examined 1335 stroke-free individuals with AF and 2683 matched controls using neuropsychological assessments and multimodal neuroimaging. The analysis revealed that individuals with AF exhibited deficits in executive function, processing speed, and reasoning, accompanied by reduced cortical thickness, elevated extracellular free-water content, and widespread white matter abnormalities, indicative of small vessel pathology. Notably, brain structural differences statistically mediated the relationship between AF and cognitive performance. DISCUSSION: Integrating a comprehensive analysis approach with extensive clinical and magnetic resonance imaging data, our study highlights small vessel pathology as a possible unifying link among AF, cognitive decline, and abnormal brain structure. These insights can inform diagnostic approaches and motivate the ongoing implementation of effective therapeutic strategies. Highlights We investigated neuropsychological and multimodal neuroimaging data of 1335 individuals with atrial fibrillation (AF) and 2683 matched controls. Our analysis revealed AF-associated deficits in cognitive domains of attention, executive function, processing speed, and reasoning. Cognitive deficits in the AF group were accompanied by structural brain alterations including reduced cortical thickness and gray matter volume, alongside increased extracellular free-water content as well as widespread differences of white matter integrity. Structural brain changes statistically mediated the link between AF and cognitive performance, emphasizing the potential of structural imaging markers as a diagnostic tool in AF-related cognitive decline.

Self-supervised learning for classifying paranasal anomalies in the maxillary sinus.

PURPOSE: Paranasal anomalies, frequently identified in routine radiological screenings, exhibit diverse morphological characteristics. Due to the diversity of anomalies, supervised learning methods require large labelled dataset exhibiting diverse anomaly morphology. Self-supervised learning (SSL) can be used to learn representations from unlabelled data. However, there are no SSL methods designed for the downstream task of classifying paranasal anomalies in the maxillary sinus (MS). METHODS: Our approach uses a 3D convolutional autoencoder (CAE) trained in an unsupervised anomaly detection (UAD) framework. Initially, we train the 3D CAE to reduce reconstruction errors when reconstructing normal maxillary sinus (MS) image. Then, this CAE is applied to an unlabelled dataset to generate coarse anomaly locations by creating residual MS images. Following this, a 3D convolutional neural network (CNN) reconstructs these residual images, which forms our SSL task. Lastly, we fine-tune the encoder part of the 3D CNN on a labelled dataset of normal and anomalous MS images. RESULTS: The proposed SSL technique exhibits superior performance compared to existing generic self-supervised methods, especially in scenarios with limited annotated data. When trained on just 10% of the annotated dataset, our method achieves an area under the precision-recall curve (AUPRC) of 0.79 for the downstream classification task. This performance surpasses other methods, with BYOL attaining an AUPRC of 0.75, SimSiam at 0.74, SimCLR at 0.73 and masked autoencoding using SparK at 0.75. CONCLUSION: A self-supervised learning approach that inherently focuses on localizing paranasal anomalies proves to be advantageous, particularly when the subsequent task involves differentiating normal from anomalous maxillary sinuses. Access our code at https://github.com/mtec-tuhh/self-supervised-paranasal-anomaly .

Reduced olfactory bulb volume accompanies olfactory dysfunction after mild SARS-CoV-2 infection.

Despite its high prevalence, the determinants of smelling impairment in COVID-19 remain not fully understood. In this work, we aimed to examine the association between olfactory bulb volume and the clinical trajectory of COVID-19-related smelling impairment in a large-scale magnetic resonance imaging (MRI) analysis. Data of non-vaccinated COVID-19 convalescents recruited within the framework of the prospective Hamburg City Health Study COVID Program between March and December 2020 were analyzed. At baseline, 233 participants underwent MRI and neuropsychological testing as well as a structured questionnaire for olfactory function. Between March and April 2022, olfactory function was assessed at follow-up including quantitative olfactometric testing with Sniffin' Sticks. This study included 233 individuals recovered from mainly mild to moderate SARS-CoV-2 infections. Longitudinal assessment demonstrated a declining prevalence of self-reported olfactory dysfunction from 67.1% at acute infection, 21.0% at baseline examination and 17.5% at follow-up. Participants with post-acute self-reported olfactory dysfunction had a significantly lower olfactory bulb volume at baseline than normally smelling individuals. Olfactory bulb volume at baseline predicted olfactometric scores at follow-up. Performance in neuropsychological testing was not significantly associated with the olfactory bulb volume. Our work demonstrates an association of long-term self-reported smelling dysfunction and olfactory bulb integrity in a sample of individuals recovered from mainly mild to moderate COVID-19. Collectively, our results highlight olfactory bulb volume as a surrogate marker that may inform diagnosis and guide rehabilitation strategies in COVID-19.

Longitudinal microstructural alterations surrounding subcortical ischemic stroke lesions detected by free-water imaging.

In this study we explore the spatio-temporal trajectory and clinical relevance of microstructural white matter changes within and beyond subcortical stroke lesions detected by free-water imaging. Twenty-seven patients with subcortical infarct with mean age of 66.73 (SD 11.57) and median initial NIHSS score of 4 (IQR 3-7) received diffusion MRI 3-5 days, 1 month, 3 months, and 12 months after symptom-onset. Extracellular free-water and fractional anisotropy of the tissue (FAT) were averaged within stroke lesions and the surrounding tissue. Linear models showed increased free-water and decreased FAT in the white matter of patients with subcortical stroke (lesion [free-water/FAT, mean relative difference in %, ipsilesional vs. contralesional hemisphere at 3-5 days, 1 month, 3 months, and 12 months after symptom-onset]: +41/-34, +111/-37, +208/-26, +251/-18; perilesional tissue [range in %]: +[5-24]/-[0.2-7], +[2-20]/-[3-16], +[5-43]/-[2-16], +[10-110]/-[2-12]). Microstructural changes were most prominent within the lesion and gradually became less pronounced with increasing distance from the lesion. While free-water elevations continuously increased over time and peaked after 12 months, FAT decreases were most evident 1 month post-stroke, gradually returning to baseline values thereafter. Higher perilesional free-water and higher lesional FAT at baseline were correlated with greater reductions in lesion size (rho = -0.51, p = .03) in unadjusted analyses only, while there were no associations with clinical measures. In summary, we find a characteristic spatio-temporal pattern of extracellular and cellular alterations beyond subcortical stroke lesions, indicating a dynamic parenchymal response to ischemia characterized by vasogenic edema, cellular damage, and white matter atrophy.

Enhancing Cognitive Performance Prediction through White Matter Hyperintensity Connectivity Assessment: A Multicenter Lesion Network Mapping Analysis of 3,485 Memory Clinic Patients.

Introduction: White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating cognitive health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. We propose that lesion network mapping (LNM), enables to infer if brain networks are connected to lesions, and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed this approach to test the following hypotheses: (1) LNM-informed markers surpass WMH volumes in predicting cognitive performance, and (2) WMH contributing to cognitive impairment map to specific brain networks. Methods & results: We analyzed cross-sectional data of 3,485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in 4 cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity across 480 atlas-based gray and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. The capacity of total and regional WMH volumes and LNM scores in predicting cognitive function was compared using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention and executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater disruptive effects of WMH on regional connectivity, in gray and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Conclusion: Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network effects, particularly in attentionrelated brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.

Computer-Aided Diagnosis of Maxillary Sinus Anomalies: Validation and Clinical Correlation.

OBJECTIVE: Computer aided diagnostics (CAD) systems can automate the differentiation of maxillary sinus (MS) with and without opacification, simplifying the typically laborious process and aiding in clinical insight discovery within large cohorts. METHODS: This study uses Hamburg City Health Study (HCHS) a large, prospective, long-term, population-based cohort study of participants between 45 and 74 years of age. We develop a CAD system using an ensemble of 3D Convolutional Neural Network (CNN) to analyze cranial MRIs, distinguishing MS with opacifications (polyps, cysts, mucosal thickening) from MS without opacifications. The system is used to find correlations of participants with and without MS opacifications with clinical data (smoking, alcohol, BMI, asthma, bronchitis, sex, age, leukocyte count, C-reactive protein, allergies). RESULTS: The evaluation metrics of CAD system (Area Under Receiver Operator Characteristic: 0.95, sensitivity: 0.85, specificity: 0.90) demonstrated the effectiveness of our approach. MS with opacification group exhibited higher alcohol consumption, higher BMI, higher incidence of intrinsic asthma and extrinsic asthma. Male sex had higher prevalence of MS opacifications. Participants with MS opacifications had higher incidence of hay fever and house dust allergy but lower incidence of bee/wasp venom allergy. CONCLUSION: The study demonstrates a 3D CNN's ability to distinguish MS with and without opacifications, improving automated diagnosis and aiding in correlating clinical data in population studies. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

A latent clinical-anatomical dimension relating metabolic syndrome to brain structure and cognition.

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.

Association of structural connectivity with functional brain network segregation in a middle-aged to elderly population.

Introduction: The deterioration of white matter pathways is one of the hallmarks of the ageing brain. In theory, this decrease in structural integrity leads to disconnection between regions of brain networks and thus to altered functional connectivity and a decrease in cognitive abilities. However, in many studies, associations between structural and functional connectivity are rather weak or not observed at all. System segregation, defined as the extent of partitioning between different resting state networks has increasingly gained attention in recent years as a new metric for functional changes in the aging brain. Yet there is a shortage of previous reports describing the association of structural integrity and functional segregation. Methods: Therefore, we used a large a large sample of 2,657 participants from the Hamburg City Health Study, a prospective population-based study including participants aged 46-78 years from the metropolitan region Hamburg, Germany. We reconstructed structural and functional connectomes to analyze whether there is an association between age-related differences in structural connectivity and functional segregation, and whether this association is stronger than between structural connectivity and functional connectivity. In a second step, we investigated the relationship between functional segregation and executive cognitive function and tested whether this association is stronger than that between functional connectivity and executive cognitive function. Results: We found a significant age-independent association between decreasing structural connectivity and decreasing functional segregation across the brain. In addition, decreasing functional segregation showed an association with decreasing executive cognitive function. On the contrary, no such association was observed between functional connectivity and structural connectivity or executive function. Discussion: These results indicate that the segregation metric is a more sensitive biomarker of cognitive ageing than functional connectivity at the global level and offers a unique and more complementary network-based explanation.

Multiple instance ensembling for paranasal anomaly classification in the maxillary sinus.

PURPOSE: Paranasal anomalies are commonly discovered during routine radiological screenings and can present with a wide range of morphological features. This diversity can make it difficult for convolutional neural networks (CNNs) to accurately classify these anomalies, especially when working with limited datasets. Additionally, current approaches to paranasal anomaly classification are constrained to identifying a single anomaly at a time. These challenges necessitate the need for further research and development in this area. METHODS: We investigate the feasibility of using a 3D convolutional neural network (CNN) to classify healthy maxillary sinuses (MS) and MS with polyps or cysts. The task of accurately localizing the relevant MS volume within larger head and neck Magnetic Resonance Imaging (MRI) scans can be difficult, but we develop a strategy which includes the use of a novel sampling technique that not only effectively localizes the relevant MS volume, but also increases the size of the training dataset and improves classification results. Additionally, we employ a Multiple Instance Ensembling (MIE) prediction method to further boost classification performance. RESULTS: With sampling and MIE, we observe that there is consistent improvement in classification performance of all 3D ResNet and 3D DenseNet architecture with an average AUPRC percentage increase of 21.86 ± 11.92% and 4.27 ± 5.04% by sampling and 28.86 ± 12.80% and 9.85 ± 4.02% by sampling and MIE, respectively. CONCLUSION: Sampling and MIE can be effective techniques to improve the generalizability of CNNs for paranasal anomaly classification. We demonstrate the feasibility of classifying anomalies in the MS. We propose a data enlarging strategy through sampling alongside a novel MIE strategy that proves to be beneficial for paranasal anomaly classification in the MS.

Association between periodontal disease and microstructural brain alterations in the Hamburg City Health Study.

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.

Brain imaging and neuropsychological assessment of individuals recovered from a mild to moderate SARS-CoV-2 infection.

As severe acute respiratory syndrome coronavirus type 2 (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 nonvaccinated 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 mo 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 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 (MD) and extracellular free water which were elevated in the white matter of post-SARS-CoV-2 individuals compared to matched controls (free water: 0.148 ± 0.018 vs. 0.142 ± 0.017, P < 0.001; MD [10-3 mm2/s]: 0.747 ± 0.021 vs. 0.740 ± 0.020, P < 0.001). 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.

A latent clinical-anatomical dimension relating metabolic syndrome to brain structure and cognition.

The link between metabolic syndrome (MetS) and neurodegenerative as well 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, cortical 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.

Association between Coffee Consumption and Brain MRI Parameters in the Hamburg City Health Study.

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 (<1 cup, 1-2 cups, 3-4 cups, 5-6 cups, >6 cups). In multiple linear regressions, we examined the association between brain MRI parameters and coffee consumption (reference group <1 cup). After adjustment for covariates, 3-4 cups of daily coffee were associated with lower PSMD (p = 0.028) and higher cortical thickness (p = 0.015) compared to <1 cup. Moreover, 1-2 cups per day was also associated with lower PSMD (p = 0.022). Associations with WMH load or other groups of coffee consumption were not significant (p > 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.

Brain network architecture constrains age-related cortical thinning.

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 pronounced age effects in sensorimotor areas. Regional age-related differences were strongly correlated within the structurally defined node neighborhood. The overall pattern of thickness differences 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 act as organizing principles behind age-related cortical thinning as an imaging surrogate of cortical atrophy.

Association of Carotid Plaque and Flow Velocity With White Matter Integrity in a Middle-aged to Elderly Population.

BACKGROUND AND OBJECTIVES: It is uncertain whether there is an association of carotid plaques (CP) and flow velocities with peak-width mean diffusivity (PSMD) and white matter hyperintensities (WMH) independent of shared risk factors. We aimed to study this association controlling for biomarkers of inflammation and cardiac dysfunction as well as typical cardiovascular risk factors and spatial distribution. METHODS: We included participant from the population-based Hamburg City Health Study, recruiting citizens between 45 and 74 years of age. Medical history was obtained from structured interviews and extended laboratory tests, physical examinations, MRI of the head, echocardiography, abdominal and carotid ultrasound were performed. We performed multivariable regression analysis with PSMD, periventricular, deep, and total volume of WMH (pWMH, dWMH, tWMH) as dependent variables. PSMD was calculated as the difference between the 95th and 5th percentile of MD values on the white skeleton in standard space Volumes of WMH were determined by application of a manually trained k-nearest neighbor segmentation algorithm. WMH measured within a distance of 1 cm from the surface of the lateral ventricles were defined as pWMH, and above 1 cm as dWMH. RESULTS: 2623 participants were included. Median age was 65 years and 56% were women. Their median tWMH was 946 mm3(IQR:419, 2164), PSMD 2.24 mm2 /s x 10-4 (IQR: 2.04,2.47), peak systolic velocity (PSV) of internal carotid arteries 0.70m/sec (IQR:0.60, 0.81), and 35% had CP. Adjusted for age, sex, high-sensitive CRP, NT-proBNP, and commonly measured cardiovascular risk and systemic hemodynamic factors, both CP (B=0.15;CI:0.04, 0.26;p=0.006) and low PSV (B=-0.49; CI:-0.87,-0.11;p=0.012) were significantly associated with a higher tWMH and PSMD. Low PSV(B=-0.48;CI:-0.87,-0.1;p=0.013) was associated with pWMH, and presence of CP with pWMH (B=0.15; CI:0.04,0.26; p=0.008) and dWMH (B=0.42; CI:0.11,0.74; p<0.009). CONCLUSION: Low PSV and CP are associated with WMH and PSMD independent of cardiovascular risk factors and biomarkers of inflammation and cardiac dysfunction. This points towards pathophysiological pathways underlying both large and small vessel disease beyond the common cardiovascular risk profile. TRIAL REGISTRATION INFORMATION: The trial was submitted at www. CLINICALTRIALS: gov, under NCT03934957 on January 4 2019. The first participant was enrolled in February 2016.

Equalization of Brain State Occupancy Accompanies Cognitive Impairment in Cerebral Small Vessel Disease.

BACKGROUND: Cognitive impairment is a hallmark of cerebral small vessel disease (cSVD). Functional magnetic resonance imaging has highlighted connections between patterns of brain activity and variability in behavior. We aimed to characterize the associations between imaging markers of cSVD, dynamic connectivity, and cognitive impairment. METHODS: We obtained magnetic resonance imaging and clinical data from the population-based Hamburg City Health Study. cSVD was quantified by white matter hyperintensities and peak-width of skeletonized mean diffusivity (PSMD). Resting-state blood oxygen level-dependent signals were clustered into discrete brain states, for which fractional occupancies (%) and dwell times (seconds) were computed. Cognition in multiple domains was assessed using validated tests. Regression analysis was used to quantify associations between white matter damage, spatial coactivation patterns, and cognitive function. RESULTS: Data were available for 979 participants (ages 45-74 years, median white matter hyperintensity volume 0.96 mL). Clustering identified five brain states with the most time spent in states characterized by activation (+) or suppression (-) of the default mode network (DMN) (fractional occupancy: DMN+ = 25.1 ± 7.2%, DMN- = 25.5 ± 7.2%). Every 4.7-fold increase in white matter hyperintensity volume was associated with a 0.95-times reduction of the odds of occupying DMN+ or DMN-. Time spent in DMN-related brain states was associated with executive function. CONCLUSIONS: Associations between white matter damage, whole-brain spatial coactivation patterns, and cognition suggest equalization of time spent in different brain states as a marker for cSVD-associated cognitive decline. Reduced gradients between brain states in association with brain damage and cognitive impairment reflect the dedifferentiation hypothesis of neurocognitive aging in a network-theoretical context.

Free-water diffusion MRI detects structural alterations surrounding white matter hyperintensities in the early stage of cerebral small vessel disease.

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.

Association of Age and Structural Brain Changes With Functional Connectivity and Executive Function in a Middle-Aged to Older Population-Based Cohort.

Aging is accompanied by structural brain changes that are thought to underlie cognitive decline and dementia. Yet little is known regarding the association between increasing age, structural brain damage, and alterations of functional brain connectivity. The aim of this study was to evaluate whether cortical thickness and white matter damage as markers of age-related structural brain changes are associated with alterations in functional connectivity in non-demented healthy middle-aged to older adults. Therefore, we reconstructed functional connectomes from resting-state functional magnetic resonance imaging (MRI) (rsfMRI) data of 976 subjects from the Hamburg City Health Study, a prospective population-based study including participants aged 45-74 years from the metropolitan region Hamburg, Germany. We performed multiple linear regressions to examine the association of age, cortical thickness, and white matter damage quantified by the peak width of skeletonized mean diffusivity (PSMD) from diffusion tensor imaging on whole-brain network connectivity and four predefined resting state networks (default mode, dorsal, salience, and control network). In a second step, we extracted subnetworks with age-related decreased functional connectivity from these networks and conducted a mediation analysis to test whether the effect of age on these networks is mediated by decreased cortical thickness or PSMD. We observed an independent association of higher age with decreased functional connectivity, while there was no significant association of functional connectivity with cortical thickness or PSMD. Mediation analysis identified cortical thickness as a partial mediator between age and default subnetwork connectivity and functional connectivity within the default subnetwork as a partial mediator between age and executive cognitive function. These results indicate that, on a global scale, functional connectivity is not determined by structural damage in healthy middle-aged to older adults. There is a weak association of higher age with decreased functional connectivity which, for specific subnetworks, appears to be mediated by cortical thickness.

Multi-organ assessment in mainly non-hospitalized individuals after SARS-CoV-2 infection: The Hamburg City Health Study COVID programme.

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.