Is CAA a perivascular brain clearance disease? A discussion of the evidence to date and outlook for future studies.

The brain's network of perivascular channels for clearance of excess fluids and waste plays a critical role in the pathogenesis of several neurodegenerative diseases including cerebral amyloid angiopathy (CAA). CAA is the main cause of hemorrhagic stroke in the elderly, the most common vascular comorbidity in Alzheimer's disease and also implicated in adverse events related to anti-amyloid immunotherapy. Remarkably, the mechanisms governing perivascular clearance of soluble amyloid ß-a key culprit in CAA-from the brain to draining lymphatics and systemic circulation remains poorly understood. This knowledge gap is critically important to bridge for understanding the pathophysiology of CAA and accelerate development of targeted therapeutics. The authors of this review recently converged their diverse expertise in the field of perivascular physiology to specifically address this problem within the framework of a Leducq Foundation Transatlantic Network of Excellence on Brain Clearance. This review discusses the overarching goal of the consortium and explores the evidence supporting or refuting the role of impaired perivascular clearance in the pathophysiology of CAA with a focus on translating observations from rodents to humans. We also discuss the anatomical features of perivascular channels as well as the biophysical characteristics of fluid and solute transport.

Mapping the functional B-cell epitopes of Shigella invasion plasmid antigen D (IpaD).

Shigella bacteria utilize the type III secretion system (T3SS) to invade host cells and establish local infection. Invasion plasmid antigen D (IpaD), a component of Shigella T3SS, has garnered extensive interest as a vaccine target, primarily due to its pivotal role in the Shigella invasion, immunogenic property, and a high degree of conservation across Shigella species and serotypes. Currently, we are developing an epitope- and structure-based multivalent vaccine against shigellosis and require functional epitope antigens of key Shigella virulence determinants including IpaD. However, individual IpaD B-cell epitopes, their contributions to the overall immunogenicity, and functional activities attributing to bacteria invasion have not been fully characterized. In this study, we predicted continuous B-cell epitopes in silico and fused each epitope to a carrier protein. Then, we immunized mice intramuscularly with each epitope fusion protein, examined the IpaD-specific antibody responses, and measured antibodies from each epitope fusion for the activity against Shigella invasion in vitro. Data showed that all epitope fusion proteins induced similar levels of anti-IpaD IgG antibodies in mice, and differences were noted for antibody inhibition activity against Shigella invasion. IpaD epitope 1 (SPGGNDGNSV), IpaD epitope 2 (LGGNGEVVLDNA), and IpaD epitope 5 (SPNNTNGSSTET) induced antibodies significantly better in inhibiting invasion from Shigella flexneri 2a, and epitopes 1 and 5 elicited antibodies more effectively at preventing invasion of Shigella sonnei. These results suggest that IpaD epitopes 1 and 5 can be the IpaD representative antigens for epitope-based polyvalent protein construction and protein-based cross-protective Shigella vaccine development.IMPORTANCEShigella is a leading cause of diarrhea in children younger than 5 years in developing countries (children's diarrhea) and continues to be a major threat to public health. No licensed vaccines are currently available against the heterogeneous Shigella species and serotype strains. Aiming to develop a cross-protective multivalent vaccine against shigellosis and dysentery, we applied novel multiepitope fusion antigen (MEFA) technology to construct a broadly immunogenic polyvalent protein antigen, by presenting functional epitopes of multiple Shigella virulence determinants on a backbone protein. The functional IpaD epitopes identified from this study will essentially allow us to construct an optimal polyvalent Shigella immunogen, leading to the development of a cross-protective vaccine against shigellosis (and dysentery) and the improvement of global health. In addition, identifying functional epitopes from heterogeneous virulence determinants and using them as antigenic representatives for the development of cross-protective multivalent vaccines can be applied generally in vaccine development.

TECH preserves global cognition of older adults with MCI compared with a control group: a randomized controlled trial.

BACKGROUND: Cognitive training using touchscreen tablet casual game applications (apps) has potential to be an effective treatment method for people with mild cognitive impairment (MCI). AIMS: This study aimed to establish the effectiveness of 'Tablet Enhancement of Cognition and Health' (TECH), a novel cognitive intervention for improving/preserving cognition in older adults with MCI. METHODS: A single-blind randomized controlled trial with assessments pre-, post-, and at 6-month follow-up was conducted. TECH entailed 5 weeks of daily self-training utilizing tablet apps, facilitated by weekly group sessions. Global cognition was assessed by the Montreal Cognitive Assessment (MoCA), and specific cognitive components were assessed using WebNeuro computerized battery. Short Form Health Survey (SF-12) assessed health-related quality of life (HRQoL). Intention-to-treat analysis was conducted and the %change was calculated between pre-post and between pre-follow-up. Cohen's d effect size was also calculated. RESULTS: Sixty-one participants aged 65-89 years were randomly allocated to TECH (N = 31, 14 women) or to standard care (N = 30, 14 women). Pre-post and pre-follow-up MoCA %change scores were significantly higher in TECH than control (U = 329.5, p < .05; U = 294.5, p < .05) with intermediate effect size values (Cohen's d = .52, Cohen's d = .66). Forty percent of TECH participants versus 6.5% of control participants achieved a minimal clinical important difference in MoCA. Pre-post between-group differences for specific cognitive components were not found and HRQoL did not change. DISCUSSION AND CONCLUSIONS: TECH encouraged daily self-training and showed to preserve global cognition of older adults with MCI. The implementation of TECH is recommended for older adults with MCI, who are at risk for further cognitive decline.

Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA), updates in 2022-2023. Cerebrovascular disease and the failure of elimination of Amyloid-ß from the brain and retina with age and Alzheimer's disease: Opportunities for therapy.

This editorial summarizes advances from the Clearance of Interstitial Fluid and Cerebrospinal Fluid (CLIC) group, within the Vascular Professional Interest Area (PIA) of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART). The overarching objectives of the CLIC group are to: (1) understand the age-related physiology changes that underlie impaired clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) (CLIC); (2) understand the cellular and molecular mechanisms underlying intramural periarterial drainage (IPAD) in the brain; (3) establish novel diagnostic tests for Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), retinal amyloid vasculopathy, amyloid-related imaging abnormalities (ARIA) of spontaneous and iatrogenic CAA-related inflammation (CAA-ri), and vasomotion; and (4) establish novel therapies that facilitate IPAD to eliminate amyloid ß (Aß) from the aging brain and retina, to prevent or reduce AD and CAA pathology and ARIA side events associated with AD immunotherapy.

Investigate the immunogenic and protective effect of trivalent chimeric protein containing IpaD-StxB-TolC antigens as a vaccine candidate against S. dysenteri and S. flexneri.

BACKGROUNDS: Shigella spp. causes bloody diarrhea and leads to death, especially in children. Chimeric proteins containing virulence factors can prevent Shigella infection. The purpose of this study is to investigate the immunogenic and protective effect of trivalent chimeric protein containing IpaD-StxB-TolC antigens against shiga toxin, S. dysenteri and S. flexneri in vitro and in vivo conditions. METHODS: Recombinant vector was transferred to E. coli BL21. The expression of the chimeric protein was confirmed by SDS PAGE and purified using the Ni-NTA column. Mice were immunized with recombinant protein and antibody titer was evaluated by ELISA. 10, 25 and 50 LD50 of Shiga toxin neutralization was evaluated in vitro (Vero cell line) and in vivo conditions. Also, the challenge of immunized mice with 10, 25 and 50 LD50 of S. dysentery and S. flexneri was done. RESULTS: The expression and purification of the recombinant protein with 60.6 kDa was done. ELISA showed increased antibody titer against the chimeric protein. MTT assay indicated that 1/8000 dilution of the sera had a 51% of cell viability against the toxin in Vero cell line. The challenge of mice immunized with toxin showed that the mice had complete protection against 10 and 25 LD50 of toxin and had 40% survival against 50 LD50. Mice receiving 10 and 25 LD50 of S. dysenteri and S. flexneri had 100% protection and in 50 LD50 the survival rate was 60 and 50%, respectively. Organ burden showed that the amount of bacterial colonization in immunized mice was 1 × 104 CFU/mL, which was significantly different from the control group. CONCLUSION: This study showed that chimeric proteins can create favorable immunogenicity in the host as vaccine candidates.

Validation of a tablet-based assessment of auditory sensitivity for researchers.

Quantifying hearing acuity is increasingly important across a wide range of research areas in the behavioral and neurosciences. Scientists have relied on either self-reported hearing status or the availability of diagnostic hearing assessment in past studies. There remains a need for a valid and reliable assessment of auditory sensitivity that can provide estimates of the magnitude of hearing loss, if present, without requirements for professional audiologists, facilities, and equipment that are needed to conduct a diagnostic hearing assessment. The goal of this experiment was to validate the NIH Toolbox® Hearing Threshold Test (HTT), a tablet-based hearing assessment available via iPad application that uses consumer-grade headphones, on a clinical sample of children and adults with varying degrees of hearing acuity. Electroacoustic analysis of the hearing assessment application and headphones demonstrated acoustic outputs within established conformity standards for hearing assessment. Twenty-seven children and 63 adults participated in a standard diagnostic hearing assessment and the experimental tablet-based assessment. The results showed that thresholds from the tablet-based assessment were highly correlated with thresholds from the clinical hearing assessment (r = .83-.93) for children and adults for all frequencies and across a range of levels of hearing acuity. The HTT also met clinical test-retest reliability standards (Cronbach's α > .86). The tablet-based hearing assessment provides acceptable estimates of hearing levels for children and adults when diagnostic audiometric assessment capabilities are not available.

Speech-language pathologists' perceptions of augmentative and alternative communication in Thailand.

Augmentative and alternative communication (AAC) systems are not well-known and broadly used in Thailand. To begin introducing AAC systems and interventions to children with complex communication needs in Thailand, understanding speech-language pathologists' (SLPs) perceptions toward various AAC systems is an important first step. This study assessed SLPs' perceptions of three AAC modalities: gestural communication, communication boards, and iPad1-based speech-output technologies. A total of 78 SLPs watched three video vignettes of a child using each mode and rated their impressions of intelligibility, ease of learnability and use, effectiveness, and preference. Then they were asked to rate factors on visual analog scales that provided additional insights into their rationales and their preferences for AAC modalities for nonverbal clients and for themselves if they were nonverbal. The results indicated that most of the SLPs rated iPad-based speech-output technologies as being the more intelligible, effective, and preferred mode of communication. Gestural communication was rated as the easiest mode to learn and use for a child with complex communication needs. Despite infrequent use of iPad-based speech-output technologies in Thailand, SLPs' ratings indicated high social acceptance of this modality for promoting communication abilities of children with complex communication needs. Results also revealed some biases and lack of knowledge about AAC systems in Thailand.

Increasing Sight-Phrase Reading with an iPad intervention for Two Students with Intellectual Disability.

Sight-word interventions are often implemented when students show delays in word recognition. However, few studies have investigated the effects of teaching sight words using phrases. The current study investigated the effects of a tablet-based flashcard intervention on the acquisition of sight phrases. A multiple-baseline design across word sets was used for two students with intellectual disability who were included in the general education classroom for the majority of the day. For each phrase, students used an iPad flashcard program and were prompted to see the phrase, say the phrase, tap the screen to hear the phrase, and then say the phrase again before moving on to the next phrase. Results showed that both students quickly acquired the ability to read the previously unknown sight phrases across three different sets of phrases. Discussion focuses on using tablet-based interventions for students with intellectual disability, particularly those included within a general education classroom.

mLearning Versus Paper and Pencil Practice for Telling Time: Impact for Attention and Accuracy.

The purpose of this study was to investigate the impact of mLearning or mobile device practice on the attention and accuracy of student's use of math concepts, specifically, telling time. A single subject, alternating treatment design was used to compare mLearning to paper and pencil practice in four 3rd grade male students. Results were mixed; two children were observed to be more on-task during the mLearning practice, and two children were observed to perform similarly across both conditions. Additionally, two children performed similarly on correctly completed problems across both conditions, and two children performed better using paper and pencil practice. All students completed more math problems during the paper and pencil practice.

How the Inflamed Skull-Box Might Ruin the Cerebello-Cerebral Social Repertoire: Imaging, Testing, Rescuing with Currents.

Nascent cerebellar neuropsychiatry is rewriting complex human relations. In daily practice this sheds light on subsets of therapy-resistant patients, who feel hampered by a lack of skills in predictively presensing the trajectories to where especially their interpersonal appropriations might end up. Humans affected by "dysmetric" social phobia often lead minimal lives, strongly dislike exposition, suffer fatiguability also from immune dysfunctions, and anhedonia. In social dysmetria especially on the cerebellar cortex`s both lateralmost Crus-II (Van Overwalle) seem damaged, the left Crus-I may add agentic failure (Guell). The cerebellum, and the basal ganglia together discipline the cortex through parallel closed circuits partly interconnected through the thalamus. "Patho-trajectories" of the cere-bellum in daily care emerge through also neurological ataxiology and MRI-imaging. A uniquely pontine axonal diffusive damage to an executive-control-loop as core of "p-factor", the prime broad risk factor, points to an immune-arterial hotspot at the root of cerebellar arterial supply, as supported by the pediatric mostly inflammatory somatic "d-factor". While localizations refer back to his "phrenology", F. G. Gall's contention, that skulls, plausibly via mycobacteria, were relevant, are rehabilitated by calvario-menigeal vessels, which added the skull to the new brain logistics. Mast cells are uniquely positioned to cause superficial and deep cortical pathologies, and, en-closed in its subtentorial posterior fossa, also the cerebellum is exposed to various, often intracellular, smoldering originally dental or ORL-infections exemplifying non-neural psychiatric etiologies.

Mobile learning: Pre-service teachers' perceptions of integrating iPads into future teaching.

This study investigated pre-service teachers' perceptions of using iPads in teaching, with a focus on motivation to adopt iPads, iPad-integration self-efficacy, and intention to adopt iPads for future teaching. Changes of pre-service teachers' perceptions of using iPads over time as well as the relationships of motivation, self-efficacy, and intention for iPad adoption were examined. Participants were pre-service teachers from a university in the northeastern United States. Data were collected using online pre- and post-surveys. Quantitative and qualitative approaches were performed to analyze the data. Results indicated that there were significant changes in pre-service teachers' motivation and intention to adopt iPads before and after their participation in a mobile learning project. Motivation and iPad-integration self-efficacy were significant predictors of pre-service teachers' intention for future adoption. iPad ownership and prior experience with iPad-integrated lesson plans were potential factors that had a significant impact on pre-service teachers' perceptions of using iPads in future teaching. Pre-service teachers' perceived advantages and disadvantages of using iPads were reported and discussed. The findings of this study not only contribute to the understanding of iPad integration among pre-service teachers, but also provide an evidence on the positive influence of iPad-integrated activities on pre-service teachers' perceptions of using iPads for future teaching.

A promising cognitive screener in multiple sclerosis: The NIH toolbox cognition battery concords with gold standard neuropsychological measures.

BACKGROUND: Routine cognitive screening is a priority in MS clinical care. The National Institutes of Health Toolbox (NIHTB) Cognition Battery is a 30-min instrument validated in neurological populations excluding MS. OBJECTIVES: To assess construct validity of NIHTB tests and compare classification of cognitive impairment with gold-standard tests. To evaluate relationships between fluid cognition and clinical measures. METHODS: Eighty-seven individuals, aged 30-59 years, completed the NIHTB, Minimal Assessment of Cognitive Function in MS (MACFIMS), Wechsler Adult Intelligence Scale-IV subtests, and measures of disease severity, depression, and fatigue. RESULTS: The NIHTB showed adequate convergent validity for processing speed, working memory, and episodic memory. Although fluid cognition scores from the NIHTB and MACFIMS classified a similar proportion of participants as cognitively impaired, the two batteries differed in which individuals were classified as impaired versus preserved. NIHTB fluid cognition was inversely correlated with disease severity but not related to depression or fatigue. CONCLUSIONS: The NIHTB concords with gold-standard measures, and classifies cognitive impairment at similar rates to the MACFIMS. Adjusted NIHTB fluid cognition was negatively associated with disease severity suggesting clinical utility. Psychometric validation of the NIHTB in clinical practice will elucidate its promise as a cognitive screener in MS.

Accuracy Verification of Surface Models of Architectural Objects from the iPad LiDAR in the Context of Photogrammetry Methods.

The creation of accurate three-dimensional models has been radically simplified in recent years by developing photogrammetric methods. However, the photogrammetric procedure requires complex data processing and does not provide an immediate 3D model, so its use during field (in situ) surveys is infeasible. This paper presents the mapping of fragments of built structures at different scales (finest detail, garden sculpture, architectural interior, building facade) by using a LiDAR sensor from the Apple iPad Pro mobile device. The resulting iPad LiDAR and photogrammetric models were compared with reference models derived from laser scanning and point measurements. For small objects with complex geometries acquired by iPad LiDAR, up to 50% of points were unaligned with the reference models, which is much more than for photogrammetric models. This was primarily due to much less frequent sampling and, consequently, a sparser grid. This simplification of object surfaces is highly beneficial in the case of walls and building facades as it smooths out their surfaces. The application potential of the IPad LiDAR Pro is severely constrained by its range cap being 5 m, which greatly limits the size of objects that can be recorded, and excludes most buildings.

The use of a tablet-based app for investigating the influence of autistic and ADHD traits on performance in a complex drawing task.

This paper describes a smart tablet-based drawing app to digitally record participants' engagement with the Rey-Osterrieth complex figure (ROCF) task, a well-characterised perceptual memory task that assesses local and global memory. Digitisation of the tasks allows for improved ecological validity, especially in children attracted to tablet devices. Further, digital translation of the tasks affords new measures, including accuracy and computation of the fine motor control kinematics employed to carry out the drawing Here, we report a feasibility study to test the relationship between two neurodevelopmental conditions: autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). The smart tablet app was employed with 39 adult participants (18-35) characterised for autistic and ADHD traits, and scored using the ROCF perceptual and organisational scoring systems. Trait scores and conditions were predictor variables in linear regression models. Positive correlations were found between the attention-to-detail, attention-switching and communication subscales of the autistic trait questionnaire and organisational scores on the ROCF task. These findings suggest that autistic traits might be linked to differential performance on the ROCF task. Novelty and future applications of the app are discussed.

The Impact of Inpatient Telemedicine on Personal Protective Equipment Savings During the COVID-19 Pandemic: Cross-sectional Study.

With the emergence of the COVID-19 pandemic and shortage of adequate personal protective equipment (PPE), hospitals implemented inpatient telemedicine measures to ensure operational readiness and a safe working environment for clinicians. The utility and sustainability of inpatient telemedicine initiatives need to be evaluated as the number of COVID-19 inpatients is expected to continue declining. In this viewpoint, we describe the use of a rapidly deployed inpatient telemedicine workflow at a large academic medical center and discuss the potential impact on PPE savings. In early 2020, videoconferencing software was installed on patient bedside iPads at two academic medical center teaching hospitals. An internal website allowed providers to initiate video calls with patients in any patient room with an activated iPad, including both COVID-19 and non-COVID-19 patients. Patients were encouraged to use telemedicine technology to connect with loved ones via native apps or videoconferencing software. We evaluated the use of telemedicine technology on patients' bedside iPads by monitoring traffic to the internal website. Between May 2020 and March 2021, there were a total of 1240 active users of the Video Visits website (mean 112.7, SD 49.0 connection events per month). Of these, 133 (10.7%) connections were made. Patients initiated 63 (47.4%) video calls with family or friends and sent 37 (27.8%) emails with videoconference connection instructions. Providers initiated a total of 33 (24.8%) video calls with the majority of calls initiated in August (n=22, 67%). There was a low level of adoption of inpatient telemedicine capability by providers and patients. With sufficient availability of PPE, inpatient providers did not find a frequent need to use the bedside telemedicine technology, despite a high census of patients with COVID-19. Compared to providers, patients used videoconferencing capabilities more frequently in September and October 2020. We did not find savings of PPE associated with the use of inpatient telemedicine.

Hurdles for adopting mobile learning devices at the outset of clinical courses.

BACKGROUND: Mobile devices provide medical students with easy access to medical information and educational resources. Since 2013, we have followed the study use of iPads among medical students. In 2016, we observed a notable drop in the mobile device usage in the first cohort of medical students entering their clinical courses. METHODS: The aim of the study was to identify the hurdles for adopting mobile devices at the beginning of the clinical courses. We examined how students evaluated their own and the clinical teachers' ability to use the iPad, how the study assignments fit into digital learning, and how students used the mobile device with patients. The data were collected with online surveys among three consecutive student cohorts and the distributions of closed-ended questions analyzed. RESULTS: Response rates ranged from 67.5 to 90.8%. Students evaluated their own ability to use the iPad as good or excellent and teachers' skills as relatively poor and wanted more digitally tailored assignments. They reported negative attitudes towards mobile device use in the clinical setting and were hesitant to use them in patient contact. Teachers seldom communicated suitable quality medical applications to students. CONCLUSIONS: Clinical teachers need support and training to implement a learning environment and assignments appropriate for mobile devices. Both students and teachers were concerned about using these devices with patients. To achieve the full potential of digitalisation in clinical courses, their use should be developed collectively with students.

Enhanced participation or just another activity? The social shaping of iPad use for youths with intellectual disabilities.

The use of smartphones and tablet devices in activities is believed to have great potential for enhancing the participation of people with intellectual disabilities. However, these technologies, in themselves, do not contribute to participation. What matters is how they are used. Employing the concept of domestication and insights gained from interviews with staff, this article examines conditions for the enhanced participation of youths with intellectual disability and how tablet devices are being integrated into social care settings, in particular.The findings reveal two approaches to tablet integration. In one approach, tablet use is an organized practice focused on technology acquisition, skills improvement and entertainment. In the other, it is integrated into existing practices as an aid to interpersonal communication. The organized digital activities create conditions for the youths to participate like non-disabled peers. The greatest potential for enabling participation with each other is when the youths themselves initiate the use of tablets.

Effect of the use of an iPad on the attention span of a child with Smith Magenis Syndrome: A single case study.

AIMS: To assess the effectiveness of iPad use on the attention span of a child with Smith Magenis Syndrome (n = 1), compared to attention span while working on the same tasks manually. METHODS: An AB design with a baseline and an intervention phase was used. Three manual tasks were chosen for the baseline, which matched the participant's intellectual age by the Early Intervention Method: a jigsaw puzzle (six pieces), a shape sorter, and matching pictures. These same tasks were performed on an iPad during the intervention phase. Six baseline and nine intervention phase films were included in the analysis. The 15 films were independently scored twice by two observers: once to observe the types of distractions that occurred (such as standing up from the chair, calling the teacher, or turning around on the chair), and a second time to measure the effective working time. RESULTS: iPad use led to a 45% decrease in the number of total distractions. The effective working time improved by 8% and showed a more consistent range compared to working on tasksbmanually. While task enjoyment was not directly measured, the observers and teachers agreed that working on the iPad appeared to be more enjoyable. CONCLUSIONS: In this single case study the participant showed that in his case iPad use can be effective in decreasing his distractions and therefore can improve his attention span. Enjoyment was higher while working with the iPad than performing tasks manually. This technology could therefore create more learning engagement for the participant, which could positively impact his behavior. Further research into iPad implementation for children with intellectual disabilities, poor fine motor skills, and/or attention deficits is needed.

iPad with iPad-based Apps: An Optimal Communications Tool in the Intensive Care Unit?

Raju GM. iPad with iPad-based Apps: An Optimal Communications Tool in the Intensive Care Unit? Indian J Crit Care Med 2021;25(11):1217-1218.

Retention of Gadolinium in Brain Parenchyma: Pathways for Speciation, Access, and Distribution. A Critical Review.

The unexpected appearance of T1 hyperintensities, mostly in the dentate nucleus and the globus pallidus, during nonenhanced MRI was reported in 2014. This effect is associated with prior repeated administrations of gadolinium (Gd)-based contrast agents (GBCAs) in patients with a functional blood-brain barrier (BBB). It is widely assumed that GBCAs do not cross the intact BBB, but the observation of these hypersignals raises questions regarding this assumption. This review critically discusses the mechanisms of Gd accumulation in the brain with regard to access pathways, Gd species, tissue distribution, and subcellular location. We propose the hypothesis that there is early access of Gd species to cerebrospinal fluid, followed by passive diffusion into the brain parenchyma close to the cerebral ventricles. When accessing areas rich in endogenous metals or phosphorus, the less kinetically stable GBCAs would dissociate, and Gd would bind to endogenous macromolecules, and/or precipitate within the brain tissue. It is also proposed that Gd species enter the brain parenchyma along penetrating cortical arteries in periarterial pial-glial basement membranes and leave the brain along intramural peri-arterial drainage (IPAD) pathways. Lastly, Gd/GBCAs may access the brain parenchyma directly from the blood through the BBB in the walls of capillaries. It is crucial to distinguish between the physiological distribution and drainage pathways for GBCAs and the possible dissociation of less thermodynamically/kinetically stable GBCAs that lead to long-term Gd deposition in the brain. LEVEL OF EVIDENCE: 5. TECHNICAL EFFICACY STAGE: 3.