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Many reports conclude nanoparticle (NP) brain entry based on bulk brain analysis. Bulk brain includes blood, cerebrospinal fluid and blood vessels within the brain contributing to the blood–brain and blood–cerebrospinal fluid barriers. Considering the brain as neurons, glia and their extracellular space (brain parenchyma), most studies did not show brain parenchymal NP entry. Blood–brain and blood–cerebrospinal fluid barriers anatomy and function are reviewed. Methods demonstrating brain parenchymal NP entry are presented. Results demonstrating bulk brain versus brain parenchymal entry are classified. Studies are reviewed, critiqued and classified to illustrate results demonstrating bulk brain versus parenchymal entry. Brain, blood and peripheral organ NP timecourses are compared and related to brain parenchymal entry evidence suggesting brain NP timecourse informs about brain parenchymal entry.

Perfusion alterations within several brain regions have been shown in multiple sclerosis patients using different magnetic resonance imaging (MRI) techniques. Furthermore, MRI-derived brain perfusion metrics have been investigated in association with multiple sclerosis phenotypes, physical disability, and cognitive impairment. However, a review focused on these aspects is still missing. Our aim was to review all the studies investigating the relationship between perfusion MRI and clinical severity during the last fifteen years to understand the clinical relevance of these findings. Perfusion differences among phenotypes were observed both with 1.5T and 3T scanners, with progressive multiple sclerosis presenting with lower perfusion values than relapsing-remitting multiple sclerosis patients. However, only 3T scanners showed a statistically significant distinction. Controversial results about the association between MRI-derived perfusion metrics and physical disability scores were found. However, the majority of the studies showed that lower brain perfusion and longer transit time are associated with more severe physical disability and worse cognitive performances.

Background Perfusing fixatives through the cerebrovascular system is the gold standard approach in animals to prepare brain tissue for spatial biomolecular profiling, circuit tracing, and ultrastructural studies such as connectomics. Translating these discoveries to humans requires examination of postmortem autopsy brain tissue. Yet banked brain tissue is routinely prepared using immersion fixation, which is a significant barrier to optimal preservation of tissue architecture. The challenges involved in adopting perfusion fixation in brain banks and the extent to which it improves histology quality are not well defined. Methodology We searched four databases to identify studies that have performed perfusion fixation in human brain tissue and screened the references of the eligible studies to identify further studies. From the included studies, we extracted data about the methods that they used, as well as any data comparing perfusion fixation to immersion fixation. The protocol was preregistered at the Open Science Framework: https://osf.io/cv3ys/ . Results We screened 4489 abstracts, 214 full-text publications, and identified 35 studies that met our inclusion criteria, which collectively reported on the perfusion fixation of 558 human brains. We identified a wide variety of approaches to perfusion fixation, including perfusion fixation of the brain in situ and ex situ, perfusion fixation through different sets of blood vessels, and perfusion fixation with different washout solutions, fixatives, perfusion pressures, and postfixation tissue processing methods. Through a qualitative synthesis of data comparing the outcomes of perfusion and immersion fixation, we found moderate confidence evidence showing that perfusion fixation results in equal or greater subjective histology quality compared to immersion fixation of relatively large volumes of brain tissue, in an equal or shorter amount of time. Conclusions This manuscript serves as a resource for investigators interested in building upon the methods and results of previous research in designing their own perfusion fixation studies in human brains or other large animal brains. We also suggest several future research directions, such as comparing the in situ and ex situ approaches to perfusion fixation, studying the efficacy of different washout solutions, and elucidating the types of brain donors in which perfusion fixation is likely to result in higher fixation quality than immersion fixation.

•We studied brain health between ages 68-74 after prenatal famine exposure.•Exposed men had smaller late-life brain volumes.•We observed altered brain perfusion in exposed individuals.•Rate of change was similar between exposed and unexposed groups.•Our results support persistent developmental effects on lifespan brain health. The consequences of harmful prenatal exposures for brain health may last a lifetime. Previous studies showed smaller adult brain volumes and altered perfusion at age 68 after prenatal famine exposure, particularly in men. To investigate whether the previously observed effects reflect persistent developmental effects or accelerated brain aging, we here studied longitudinal changes in brain volumes, white matter integrity, white matter hyperintensities and perfusion between ages 68 and 74 in individuals exposed and unexposed to famine in early gestation. Brain MRI scans were obtained at age 68 (n = 118; 41 exposed to famine in early gestation) and 74 (n = 81; 25 exposed) in participants of the Dutch famine birth cohort (total n = 129, longitudinal n = 70; 23 exposed). We assessed longitudinal change in brain volumes (T1w), white matter hyperintensities (FLAIR), white matter integrity (DTI) and cerebral blood flow (ASL) between those exposed in early gestation and those unexposed (born before or conceived after the famine). In longitudinal models, aging-related changes were observed between ages 68 and 74. We observed significantly smaller brain volumes in exposed compared to unexposed men, and alterations in cerebral blood flow in both exposed men and women compared to unexposed individuals. We observed no group differences in rate of brain health changes over time. Our results support prenatal famine exposure affecting brain structure and perfusion across the lifespan. The absence of group differences in rate of change over time supports a hypothesis of persistent developmental effects rather than accelerated brain aging after prenatal famine exposure.

Low intensity, transcranial focused ultrasound (tFUS) is a re-emerging brain stimulation technique with the unique capability of reaching deep brain structures non-invasively. We sought to demonstrate that tFUS can selectively and accurately target and modulate deep brain structures in humans important for emotional functioning as well as learning and memory. We hypothesized that tFUS would result in significant longitudinal changes in perfusion in the targeted brain region as well as selective modulation of BOLD activity and BOLD-based functional connectivity of the target region. In this study, we collected MRI before, simultaneously during, and after tFUS of two deep brain structures on different days in sixteen healthy adults each serving as their own control. Using longitudinal arterial spin labeling (ASL) MRI and simultaneous blood oxygen level dependent (BOLD) functional MRI, we found changes in cerebral perfusion, regional brain activity and functional connectivity specific to the targeted regions of the amygdala and entorhinal cortex (ErC). tFUS selectively increased perfusion in the targeted brain region and not in the contralateral homolog or either bilateral control region. Additionally, tFUS directly affected BOLD activity in a target specific fashion without engaging auditory cortex in any analysis. Finally, tFUS resulted in selective modulation of the targeted functional network connectivity. We demonstrate that tFUS can selectively modulate perfusion, neural activity and connectivity in deep brain structures and connected networks. Lack of auditory cortex findings suggests that the mechanism of tFUS action is not due to auditory or acoustic startle response but rather a direct neuromodulatory process. Our findings suggest that tFUS has the potential for future application as a novel therapy in a wide range of neurological and psychiatric disorders associated with subcortical pathology.

•We detect age-related arterial transit time (ATT) and ATT-corrected CBF patterns.•ATT increases with age in the frontal, temporoparietal, and occipital regions.•Without ATT correction, age-related CBF patterns generated artifact regions.•The findings emphasize ATT's role and its importance in CBF measurement for aging. Normal aging has been associated with increased arterial transit time (ATT) and reduced cerebral blood flow (CBF). However, age-related patterns of ATT and CBF and their relationship remain unclear. This is partly due to the lengthy scan times required for ATT measurements, which caused previous age-related CBF studies to not fully account for transit time. In this work, we aimed to elucidate age-related ATT and ATT-corrected CBF patterns. We examined 131 healthy subjects aged 19 to 82 years old using two pseudo-continuous arterial spin labeling (PCASL) MRI scans: one to measure fast low-resolution ATT maps with five post-labeling delays and the other to measure high-resolution perfusion-weighted maps with a single post-labeling delay. Both ATT and perfusion-weighed maps were applied with vessel suppression. We found that ATT increases with age in the frontal, temporoparietal, and occipital regions, with a more pronounced elongation in males compared to females in the middle temporal gyrus. ATT-corrected CBF decreases with age in several brain regions, including the anterior cingulate, insula, posterior cingulate, angular, precuneus, supramarginal, frontal, parietal, superior and middle temporal, occipital, and cerebellar regions, while remaining stable in the inferior temporal and subcortical regions. In contrast, without ATT correction, we detected artifactual decreases in the inferior temporal and precentral regions. These findings suggest that ATT provides valuable and independent insights into microvascular deficits and should be incorporated into CBF measurements for studies involving aging populations.

Perfusion imaging is extensively utilized to assess hemodynamic status and tissue perfusion in various organs. Computed tomography perfusion (CTP) imaging plays a key role in the early assessment and planning of stroke treatment. While CTP provides essential perfusion parameters to identify abnormal blood flow in the brain. However, CTP can be expensive with limited accessibility, and the use of contrast agents in CTP can lead to allergic reactions and adverse side effects. To address these challenges, we propose a novel deep learning framework called Multitask Automated Generation of Intermodal CT perfusion maps (MAGIC). This framework combines generative artificial intelligence and physiological information to map non-contrast computed tomography (CT) imaging to multiple contrast-free CTP imaging maps. We demonstrate enhanced image fidelity by incorporating physiological characteristics into the loss terms. Our network was trained and validated using CT image data from patients referred for stroke at UF Health and demonstrated robustness to abnormalities in brain perfusion activity. A double-blinded study was conducted involving seven experienced neuroradiologists and vascular neurologists. This study validated MAGIC's visual quality and diagnostic accuracy showing favorable performance compared to clinical perfusion imaging with intravenous contrast injection. Overall, MAGIC holds great promise in revolutionizing healthcare by offering contrast-free, cost-effective, and rapid perfusion imaging.

Adequate cerebral blood flow (CBF) is essential to proper brain development and function. Detailed characterization of CBF developmental trajectories will lead to better understanding of the development of cognitive, motor, and sensory functions, as well as behaviour in children. Previous studies have shown CBF increases during infancy and decreases during adolescence; however, the trajectories during childhood, and in particular the timing of peak CBF, remain unclear. Here, we used arterial spin labeling to map age-related changes of CBF across a large longitudinal sample that included 279 scans on 96 participants (46 girls and 50 boys) aged 2–7 years. CBF maps were analyzed using hierarchical linear regression for every voxel inside the grey matter mask, controlling for multiple comparisons. The results revealed a significant positive linear association between CBF and age in distributed brain regions including prefrontal, temporal, parietal, and occipital cortex, and in the cerebellum. There were no differences in developmental trajectories between males and females. Our findings show that CBF continues to increase until the age of 7 years, likely supporting ongoing improvements in behaviour, cognition, motor, and sensory functions in early childhood. •We measured cerebral blood flow (CBF) using arterial spin labeling.•We examined 279 scans from 96 children aged 2–7 years.•CBF increased linearly in distributed brain areas, showing that CBF peaks after age 7.•Global CBF increased 5.9% across the entire age range.•There were no significant differences between males and females.

INTRODUCTION We assessed pseudo‐continuous arterial spin labeling (pCASL) sensitivity to detect changes in cerebral blood flow (CBF) in adults with Down syndrome (DS) along the Alzheimer's disease (AD) continuum and explored the similarity with sporadic AD (sAD) hypoperfusion profile. METHODS Fifty‐one euploid cognitively unimpaired individuals, 54 adults with DS (34.54% symptomatic for AD), and 25 sAD patients underwent 3T magnetic resonance imaging. pCASL images were preprocessed using ASLprep. Analyses explored, globally and regionally, the effects of demographic variables, clinical stages, and AD biomarkers. RESULTS Age and sex differently impacted CBF in euploids versus the DS population. Asymptomatic DS showed temporo‐parietal hypoperfusion, extending into frontal areas in symptomatic cases. This pattern closely resembled sAD's pattern and correlated with AD biomarkers. DISCUSSION Adults with DS present CBF changes before symptom onset, primarily affecting posterior regions as in sAD. pCASL is a sensitive imaging modality that captures early AD‐related functional abnormalities in DS. Highlights Perfusion is negatively affected by age and correlates with Alzheimer's disease (AD) biomarkers in Down syndrome (DS). Hypoperfusion in DS was observed even before the onset of the AD clinical symptoms. The pattern of hypoperfusion in the DS population resembles the one observed in the sporadic AD population.