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Age-related differences in cortical microstructure are used to understand the neuronal mechanisms that underlie human brain ageing. The cerebral vasculature contributes to cortical ageing, but its precise interaction with cortical microstructure is poorly understood. In a cross-sectional study, we combine venous imaging with vessel distance mapping to investigate the interaction between venous distances and age-related differences in the microstructural architecture of the primary somatosensory cortex, the primary motor cortex and additional areas in the frontal cortex as non-sensorimotor control regions. We scanned 18 younger adults and 17 older adults using 7 Tesla MRI to measure age-related changes in longitudinal relaxation time (T1) and quantitative susceptibility mapping (QSM) values at 0.5 mm isotropic resolution. We modelled different cortical depths using an equi-volume approach and assessed the distance of each voxel to its nearest vein using vessel distance mapping. Our data reveal a dependence of cortical quantitative T1 values and positive QSM values on venous distance. In addition, there is an interaction between venous distance and age on quantitative T1 values, driven by lower quantitative T1 values in older compared to younger adults in voxels that are closer to a vein. Together, our data show that the local venous architecture explains a significant amount of variance in standard measures of cortical microstructure and should be considered in neurobiological models of human brain organisation and cortical ageing., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: While several studies in cerebral amyloid angiopathy (CAA) focus on cognitive function, data on neuropsychiatric symptoms (NPS) and lifelong mental activities in these patients are scarce. Since NPS are associated with functional impairment, faster cognitive decline and faster progression to death, replication studies in more diverse settings and samples are warranted., Methods: We prospectively recruited n = 69 CAA patients and n = 18 cognitively normal controls (NC). The number and severity of NPS were assessed using the Alzheimer's Disease (AD) Assessment Scale's (ADAS) noncognitive subscale. We applied different regression models exploring associations between NPS number or severity and group status (CAA vs. NC), CAA severity assessed with magnetic resonance imaging (MRI) or cognitive function (Mini-Mental State Examination (MMSE), ADAS cognitive subscale), adjusting for age, sex, years of education, arterial hypertension, AD pathology, and apolipoprotein E status. Mediation analyses were performed to test indirect effects of lifelong mental activities on CAA severity and NPS., Results: Patients with CAA had 4.86 times (95% CI 2.20-10.73) more NPS and 3.56 units (95% CI 1.94-5.19) higher expected NPS severity than NC. Higher total CAA severity on MRI predicted 1.14 times (95% CI 1.01.-1.27) more NPS and 0.57 units (95% CI 0.19-0.95) higher expected NPS severity. More severe white matter hyperintensities were associated with 1.21 times more NPS (95% CI 1.05-1.39) and 0.63 units (95% CI 0.19-1.08) more severe NPS. NPS number (MMSE mean difference - 1.15, 95% CI -1.67 to -0.63; ADAS cognitive mean difference 1.91, 95% CI 1.26-2.56) and severity (MMSE - 0.55, 95% CI -0.80 to -0.30; ADAS cognitive mean difference 0.89, 95% CI 0.57-1.21) predicted lower cognitive function. Greater lifelong mental activities partially mediated the relationship between CAA severity and NPS (indirect effect 0.05, 95% CI 0.0007-0.13), and greater lifelong mental activities led to less pronounced CAA severity and thus to less NPS (indirect effect - 0.08, 95% CI -0.22 to -0.002)., Discussion: This study suggests that NPS are common in CAA, and that this relationship may be driven by CAA severity. Furthermore, NPS seem to be tied to lower cognitive function. However, lifelong mental activities might mitigate the impact of NPS in CAA., (© 2024. The Author(s).)

Magnetic resonance angiography (MRA) performed at ultra-high magnetic field provides a unique opportunity to study the arteries of the living human brain at the mesoscopic level. From this, we can gain new insights into the brain's blood supply and vascular disease affecting small vessels. However, for quantitative characterization and precise representation of human angioarchitecture to, for example, inform blood-flow simulations, detailed segmentations of the smallest vessels are required. Given the success of deep learning-based methods in many segmentation tasks, we here explore their application to high-resolution MRA data, and address the difficulty of obtaining large data sets of correctly and comprehensively labelled data. We introduce VesselBoost , a vessel segmentation package, which utilizes deep learning and imperfect training labels for accurate vasculature segmentation. Combined with an innovative data augmentation technique, which leverages the resemblance of vascular structures, VesselBoost enables detailed vascular segmentations.

Inferior frontal sulcal hyperintensities (IFSHs) on fluid-attenuated inversion recovery (FLAIR) sequences have been proposed to be indicative of glymphatic dysfunction. Replication studies in large and diverse samples are nonetheless needed to confirm them as an imaging biomarker. We investigated whether IFSHs were tied to Alzheimer's disease (AD) pathology and cognitive performance. We used data from 361 participants along the AD continuum, who were enrolled in the multicentre DELCODE study. The IFSHs were rated visually based on FLAIR magnetic resonance imaging. We performed ordinal regression to examine the relationship between the IFSHs and cerebrospinal fluid-derived amyloid positivity and tau positivity (Aβ42/40 ratio ≤ 0.08; pTau181 ≥ 73.65 pg/mL) and linear regression to examine the relationship between cognitive performance (i.e., Mini-Mental State Examination and global cognitive and domain-specific performance) and the IFSHs. We controlled the models for age, sex, years of education, and history of hypertension. The IFSH scores were higher in those participants with amyloid positivity (OR: 1.95, 95% CI: 1.05-3.59) but not tau positivity (OR: 1.12, 95% CI: 0.57-2.18). The IFSH scores were higher in older participants (OR: 1.05, 95% CI: 1.00-1.10) and lower in males compared to females (OR: 0.44, 95% CI: 0.26-0.76). We did not find sufficient evidence linking the IFSH scores with cognitive performance after correcting for demographics and AD biomarker positivity. IFSHs may reflect the aberrant accumulation of amyloid β beyond age.

Vascular risk factors such as chronic hypertension are well-established major modifiable factors for the development of cerebral small vessel disease (cSVD). In the present study, our focus was the investigation of cSVD-related phenotypic changes in microglia in human disease and in the spontaneously hypertensive stroke-prone rat (SHRSP) model of cSVD. Our examination of cortical microglia in human post-mortem cSVD cortical tissue revealed distinct morphological microglial features specific to cSVD. We identified enlarged somata, an increase in the territory occupied by thickened microglial processes, and an expansion in the number of vascular-associated microglia. In parallel, we characterized microglia in a rodent model of hypertensive cSVD along different durations of arterial hypertension, i.e., early chronic and late chronic hypertension. Microglial somata were already enlarged in early hypertension. In contrast, at late-stage chronic hypertension, they further exhibited elongated branches, thickened processes, and a reduced ramification index, mirroring the findings in human cSVD. An unbiased multidimensional flow cytometric analysis revealed phenotypic heterogeneity among microglia cells within the hippocampus and cortex. At early-stage hypertension, hippocampal microglia exhibited upregulated CD11b/c, P2Y12R, CD200R, and CD86 surface expression. Detailed analysis of cell subpopulations revealed a unique microglial subset expressing CD11b/c, CD163, and CD86 exclusively in early hypertension. Notably, even at early-stage hypertension, microglia displayed a higher association with cerebral blood vessels. We identified several profound clusters of microglia expressing distinct marker profiles at late chronic hypertensive states. In summary, our findings demonstrate a higher vulnerability of the hippocampus, stage-specific microglial signatures based on morphological features, and cell surface protein expression in response to chronic arterial hypertension. These results indicate the diversity within microglia sub-populations and implicate the subtle involvement of microglia in cSVD pathogenesis., (© 2023. The Author(s).)

The association between cerebral blood supply and cognition has been widely discussed in the recent literature. One focus of this discussion has been the anatomical variability of the circle of Willis, with morphological differences being present in more than half of the general population. While previous studies have attempted to classify these differences and explore their contribution to hippocampal blood supply and cognition, results have been controversial. To disentangle these previously inconsistent findings, we introduce Vessel Distance Mapping (VDM) as a novel methodology for evaluating blood supply, which allows for obtaining vessel pattern metrics with respect to the surrounding structures, extending the previously established binary classification into a continuous spectrum. To accomplish this, we manually segmented hippocampal vessels obtained from high-resolution 7T time-of-flight MR angiographic imaging in older adults with and without cerebral small vessel disease, generating vessel distance maps by computing the distances of each voxel to its nearest vessel. Greater values of VDM-metrics, which reflected higher vessel distances, were associated with poorer cognitive outcomes in subjects affected by vascular pathology, while this relation was not observed in healthy controls. Therefore, a mixed contribution of vessel pattern and vessel density is proposed to confer cognitive resilience, consistent with previous research findings. In conclusion, VDM provides a novel platform, based on a statistically robust and quantitative method of vascular mapping, for addressing a variety of clinical research questions., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

This scientific commentary refers to 'Functional connectivity in older adults-the effect of cerebral small vessel disease' by Drenth et al. (https://doi.org/10.1093/braincomms/fcad126)., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Brain vascular health appears to be critical for preventing the development of amyotrophic lateral sclerosis (ALS) and slowing its progression. ALS patients often demonstrate cardiovascular risk factors and commonly suffer from cerebrovascular disease, with evidence of pathological alterations in their small cerebral blood vessels. Impaired vascular brain health has detrimental effects on motor neurons: vascular endothelial growth factor levels are lowered in ALS, which can compromise endothelial cell formation and the integrity of the blood-brain barrier. Increased turnover of neurovascular unit cells precedes their senescence, which, together with pericyte alterations, further fosters the failure of toxic metabolite removal. We here provide a comprehensive overview of the pathogenesis of impaired brain vascular health in ALS and how novel magnetic resonance imaging techniques can aid its detection. In particular, we discuss vascular patterns of blood supply to the motor cortex with the number of branches from the anterior and middle cerebral arteries acting as a novel marker of resistance and resilience against downstream effects of vascular risk and events in ALS. We outline how certain interventions adapted to patient needs and capabilities have the potential to mechanistically target the brain microvasculature towards favorable motor cortex blood supply patterns. Through this strategy, we aim to guide novel approaches to ALS management and a better understanding of ALS pathophysiology.

Background: Cerebral microbleeds (MBs) are a hallmark of cerebral small vessel disease (CSVD) and can be found on T2 * -weighted sequences on MRI. Quantitative susceptibility mapping (QSM) is a postprocessing method that also enables MBs identification and furthermore allows to differentiate them from calcifications., Aims: We explored the implications of using QSM at submillimeter resolution for MBs detection in CSVD., Methods: Both 3 and 7 Tesla (T) MRI were performed in elderly participants without MBs and patients with CSVD. MBs were quantified on T2 * -weighted imaging and QSM. Differences in the number of MBs were assessed, and subjects were classified in CSVD subgroups or controls both on 3T T2 * -weighted imaging and 7T QSM., Results: 48 participants [mean age (SD) 70.9 (8.8) years, 48% females] were included: 31 were healthy controls, 6 probable cerebral amyloid angiopathy (CAA), 9 mixed CSVD, and 2 were hypertensive arteriopathy [HA] patients. After accounting for the higher number of MBs detected at 7T QSM (Median = Mdn; Mdn 7T-QSM = 2.5; Mdn 3T-T2 = 0; z = 4.90; p < 0.001) and false positive MBs (6.1% calcifications), most healthy controls (80.6%) demonstrated at least one MB and more MBs were discovered in the CSVD group., Conclusions: Our observations suggest that QSM at submillimeter resolution improves the detection of MBs in the elderly human brain. A higher prevalence of MBs than so far known in healthy elderly was revealed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Perosa, Rotta, Yakupov, Kuijf, Schreiber, Oltmer, Mattern, Heinze, Düzel and Schreiber.)

Autism was formally recognized by the medical community in the first half of the twentieth century. Almost 100 years later, a small but growing literature has reported sex differences in the behavioral expression of autism. Recent research has also begun to explore the internal experiences of individuals with autism, including social and emotional insight. The current study examines sex differences in language-based markers of social and emotional insight in girls and boys with autism and non-autistic peers during semi-structured clinical interviews. Sixty-four participants aged 5 to 17 years were individually matched on chronological age and full-scale IQ to form four groups: autistic girls, autistic boys, non-autistic girls, and non-autistic boys. Transcribed interviews were scored using four scales that index aspects of social and emotional insight. Results revealed the main effects of diagnosis, such that youth with autism exhibited lower insight than non-autistic youth on scales indexing social cognition and object relations, emotional investment, and social causality. With regards to sex differences, across diagnoses, girls were rated higher than boys on the social cognition and object relations, emotional investment, and social causality scales. Examined within each diagnosis separately, clear sex differences emerged: both autistic and non-autistic girls demonstrated better social cognition and understanding of social causality than boys in their respective diagnostic groups. No within-diagnosis sex differences were found on the emotional insight scales, however. These results suggest that relatively enhanced social cognition and understanding of social causality in girls may be a population-level sex difference that is preserved in autism, despite the core social challenges that characterize this condition. The current findings reveal critical new information about insight into social and emotional thinking and relationships in autistic girls versus boys that have important implications for improving identification and designing effective interventions., (© 2023. The Author(s).)

Blood vessels of the brain provide the human brain with the required nutrients and oxygen. As a vulnerable part of the cerebral blood supply, pathology of small vessels can cause serious problems such as Cerebral Small Vessel Diseases (CSVD). It has also been shown that CSVD is related to neurodegeneration, such as Alzheimer's disease. With the advancement of 7 Tesla MRI systems, higher spatial image resolution can be achieved, enabling the depiction of very small vessels in the brain. Non-Deep Learning-based approaches for vessel segmentation, e.g., Frangi's vessel enhancement with subsequent thresholding, are capable of segmenting medium to large vessels but often fail to segment small vessels. The sensitivity of these methods to small vessels can be increased by extensive parameter tuning or by manual corrections, albeit making them time-consuming, laborious, and not feasible for larger datasets. This paper proposes a deep learning architecture to automatically segment small vessels in 7 Tesla 3D Time-of-Flight (ToF) Magnetic Resonance Angiography (MRA) data. The algorithm was trained and evaluated on a small imperfect semi-automatically segmented dataset of only 11 subjects; using six for training, two for validation, and three for testing. The deep learning model based on U-Net Multi-Scale Supervision was trained using the training subset and was made equivariant to elastic deformations in a self-supervised manner using deformation-aware learning to improve the generalisation performance. The proposed technique was evaluated quantitatively and qualitatively against the test set and achieved a Dice score of 80.44 ± 0.83. Furthermore, the result of the proposed method was compared against a selected manually segmented region (62.07 resultant Dice) and has shown a considerable improvement (18.98%) with deformation-aware learning.

The pial arterial vasculature of the human brain is the only blood supply to the neocortex, but quantitative data on the morphology and topology of these mesoscopic arteries (diameter 50-300 µm) remains scarce. Because it is commonly assumed that blood flow velocities in these vessels are prohibitively slow, non-invasive time-of-flight magnetic resonance angiography (TOF-MRA)-which is well suited to high 3D imaging resolutions-has not been applied to imaging the pial arteries. Here, we provide a theoretical framework that outlines how TOF-MRA can visualize small pial arteries in vivo, by employing extremely small voxels at the size of individual vessels. We then provide evidence for this theory by imaging the pial arteries at 140 µm isotropic resolution using a 7 Tesla (T) magnetic resonance imaging (MRI) scanner and prospective motion correction, and show that pial arteries one voxel width in diameter can be detected. We conclude that imaging pial arteries is not limited by slow blood flow, but instead by achievable image resolution. This study represents the first targeted, comprehensive account of imaging pial arteries in vivo in the human brain. This ultra-high-resolution angiography will enable the characterization of pial vascular anatomy across the brain to investigate patterns of blood supply and relationships between vascular and functional architecture., Competing Interests: SB, HM, MB, SR, DP, OS, JP No competing interests declared, (© 2022, Bollmann et al.)

Background and Purpose: Cerebral small vessel disease contributes to stroke and cognitive impairment and interacts with Alzheimer disease pathology. Because of the small dimensions of the affected vessels, in vivo characterization of blood flow properties is challenging but important to unravel the underlying mechanisms of the disease., Materials and Methods: A 2D phase-contrast sequence at 7T MR imaging was used to assess blood flow velocity and the pulsatility index of the perforating basal ganglia arteries. We included patients with cerebral amyloid angiopathy ( n = 8; identified through the modified Boston criteria), hypertensive arteriopathy ( n = 12; identified through the presence of strictly deep or mixed cerebral microbleeds), and age- and sex-matched controls ( n = 28; no cerebral microbleeds)., Results: Older age was related to a greater pulsatility index, irrespective of cerebral small vessel disease. In hypertensive arteriopathy, there was an association between lower blood flow velocity of the basal ganglia and the presence of peri-basal ganglia WM hyperintensities., Conclusions: Our results suggest that age might be the driving factor for altered cerebral small vessel hemodynamics. Furthermore, this study puts cerebral small vessel disease downstream pathologies in the basal ganglia region in relation to blood flow characteristics of the basal ganglia microvasculature., (© 2022 by American Journal of Neuroradiology.)

Primary visual cortex (V1) in humans is known to represent both veridically perceived external input and internally-generated contents underlying imagery and mental rotation. However, it is unknown how the brain keeps these contents separate thus avoiding a mixture of the perceived and the imagined which could lead to potentially detrimental consequences. Inspired by neuroanatomical studies showing that feedforward and feedback connections in V1 terminate in different cortical layers, we hypothesized that this anatomical compartmentalization underlies functional segregation of external and internally-generated visual contents, respectively. We used high-resolution layer-specific fMRI to test this hypothesis in a mental rotation task. We found that rotated contents were predominant at outer cortical depth bins (i.e. superficial and deep). At the same time perceived contents were represented stronger at the middle cortical bin. These results identify how through cortical depth compartmentalization V1 functionally segregates rather than confuses external from internally-generated visual contents. These results indicate that feedforward and feedback manifest in distinct subdivisions of the early visual cortex, thereby reflecting a general strategy for implementing multiple cognitive functions within a single brain region., (© 2021. The Author(s).)

The hippocampus within the medial temporal lobe is highly vulnerable to age-related pathology such as vascular disease. We examined hippocampal vascularization patterns by harnessing the ultra-high resolution of 7 Tesla magnetic resonance angiography. Dual-supply hemispheres with a contribution of the anterior choroidal artery to hippocampal blood supply were distinguished from single-supply ones with a sole dependence on the posterior cerebral artery. A recent study indicated that a dual vascular supply is related to preserved cognition and structural hippocampal integrity in old age and vascular disease. Here, we examined the regional specificity of these structural benefits at the level of medial temporal lobe sub-regions and hemispheres. In a cross-sectional study with an older cohort of 17 patients with cerebral small vessel disease (70.7  ±  9.0 years, 35.5% female) and 27 controls (71.1  ±  8.2 years, 44.4% female), we demonstrate that differences in grey matter volumes related to the hippocampal vascularization pattern were specifically observed in the anterior hippocampus and entorhinal cortex. These regions were especially bigger in dual-supply hemispheres, but also seemed to benefit from a contralateral dual supply. We further show that total grey matter volumes were greater in people with at least one dual-supply hemisphere, indicating that the hippocampal vascularization pattern has more far-reaching structural implications beyond the medial temporal lobe. A mediation analysis identified total grey matter as a mediator of differences in global cognition. However, our analyses on multiple neuroimaging markers for cerebral small vessel disease did not reveal any evidence that an augmented hippocampal vascularization conveys resistance nor resilience against vascular pathology. We propose that an augmented hippocampal vascularization might contribute to maintaining structural integrity in the brain and preserving cognition despite age-related degeneration. As such, the binary hippocampal vascularization pattern could have major implications for brain structure and function in ageing and dementia independent of vascular pathology, while presenting a simple framework with potential applicability to the clinical setting., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Here, we present an extension to our previously published structural ultrahigh resolution T 1 -weighted magnetic resonance imaging (MRI) dataset with an isotropic resolution of 250 µm, consisting of multiple additional ultrahigh resolution contrasts. Included are up to 150 µm Time-of-Flight angiography, an updated 250 µm structural T 1 -weighted reconstruction, 330 µm quantitative susceptibility mapping, up to 450 µm structural T 2 -weighted imaging, 700 µm T 1 -weighted back-to-back scans, 800 µm diffusion tensor imaging, one hour continuous resting-state functional MRI with an isotropic spatial resolution of 1.8 mm as well as more than 120 other structural T 1 -weighted volumes together with multiple corresponding proton density weighted acquisitions collected over ten years. All data are from the same participant and were acquired on the same 7 T scanner. The repository contains the unprocessed data as well as (pre-)processing results. The data were acquired in multiple studies with individual goals. This is a unique and comprehensive collection comprising a "human phantom" dataset. Therefore, we compiled, processed, and structured the data, making them publicly available for further investigation.

Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer's disease, atypical neurodegenerative dementias and Parkinson's disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

We present an ultrahigh resolution in vivo human brain magnetic resonance imaging (MRI) dataset. It consists of T 1 -weighted whole brain anatomical data acquired at 7 Tesla with a nominal isotropic resolution of 250 μm of a single young healthy Caucasian subject and was recorded using prospective motion correction. The raw data amounts to approximately 1.2 TB and was acquired in eight hours total scan time. The resolution of this dataset is far beyond any previously published in vivo structural whole brain dataset. Its potential use is to build an in vivo MR brain atlas. Methods for image reconstruction and image restoration can be improved as the raw data is made available. Pre-processing and segmentation procedures can possibly be enhanced for high magnetic field strength and ultrahigh resolution data. Furthermore, potential resolution induced changes in quantitative data analysis can be assessed, e.g., cortical thickness or volumetric measures, as high quality images with an isotropic resolution of 1 and 0.5 mm of the same subject are included in the repository as well.

The effect of captopril mediated afterload reduction on aortic regurgitation was investigated in 10 patients. Regurgitation was quantitated by means of the regurgitation fraction and the relation of regurgitant volume to end diastolic volume. These variables were derived from gated radionuclide ventriculography. After captopril treatment the blood concentration of angiotensin I rose whereas that of angiotensin II fell significantly. The conversion of angiotensin I to II was reduced to about 50% of the control value. Whereas blood pressure and heart rate did not change significantly, the regurgitation fraction and the regurgitant volume, normalised to end diastolic volume, were significantly reduced by captopril treatment. The ejection fraction remained essentially unchanged. These findings suggest that captopril reduces aortic regurgitation by reducing afterload.