Quantification of mediation effects of white matter functional characteristics on cognitive decline in aging.

Cognitive decline with aging involves multifactorial processes, including changes in brain structure and function. This study focuses on the role of white matter functional characteristics, as reflected in blood oxygenation level-dependent signals, in age-related cognitive deterioration. Building on previous research confirming the reproducibility and age-dependence of blood oxygenation level-dependent signals acquired via functional magnetic resonance imaging, we here employ mediation analysis to test if aging affects cognition through white matter blood oxygenation level-dependent signal changes, impacting various cognitive domains and specific white matter regions. We used independent component analysis of resting-state blood oxygenation level-dependent signals to segment white matter into coherent hubs, offering a data-driven view of white matter's functional architecture. Through correlation analysis, we constructed a graph network and derived metrics to quantitatively assess regional functional properties based on resting-state blood oxygenation level-dependent fluctuations. Our analysis identified significant mediators in the age-cognition relationship, indicating that aging differentially influences cognitive functions by altering the functional characteristics of distinct white matter regions. These findings enhance our understanding of the neurobiological basis of cognitive aging, highlighting the critical role of white matter in maintaining cognitive integrity and proposing new approaches to assess interventions targeting cognitive decline in older populations.

Functional modulation of lysophosphatidic acid type 2 G-protein coupled receptor facilitates alveolar bone formation.

Lipid biosynthesis is recently studied its functions in a range of cellular physiology including differentiation and regeneration. However, it still remains to be elucidated in its precise function. To reveal this, we evaluated the roles of lysophosphatidic acid (LPA) signaling in alveolar bone formation using the LPA type 2 receptor (LPAR2) antagonist AMG-35 (Amgen Compound 35) using tooth loss without periodontal disease model which would be caused by trauma and usually requires a dental implant to restore masticatory function. In this study, in vitro cell culture experiments in osteoblasts and periodontal ligament fibroblasts revealed cell type-specific responses, with AMG-35 modulating osteogenic differentiation in osteoblasts in vitro. To confirm the in vivo results, we employed a mouse model of tooth loss without periodontal disease. Five to 10 days after tooth extraction, AMG-35 facilitated bone formation in the tooth root socket as measured by immunohistochemistry for differentiation markers KI67, Osteocalcin, Periostin, RUNX2, transforming growth factor beta 1 (TGF-ß1) and SMAD2/3. The increased expression and the localization of these proteins suggest that AMG-35 elicits osteoblast differentiation through TGF-ß1 and SMAD2/3 signaling. These results indicate that LPAR2/TGF-ß1/SMAD2/3 represents a new signaling pathway in alveolar bone formation and that local application of AMG-35 in traumatic tooth loss can be used to facilitate bone regeneration and healing for further clinical treatment.

White matter engagement in brain networks assessed by integration of functional and structural connectivity.

Current models of brain networks may potentially be improved by integrating our knowledge of structural connections, within and between circuits, with metrics of functional interactions between network nodes. The former may be obtained from diffusion MRI of white matter (WM), while the latter may be derived by measuring correlations between resting state BOLD signals from pairs of gray matter (GM) regions. From inspection of diffusion MRI data, it is clear that each WM voxel within a 3D image array may be traversed by multiple WM structural tracts, each of which connects a pair of GM nodes. We hypothesized that by appropriately weighting and then integrating the functional connectivity of each such connected pair, the overall engagement of any WM voxel in brain functions could be evaluated. This model introduces a structural constraint to earlier studies of WM engagement and addresses some limitations of previous efforts to relate structure and function. Using concepts derived from graph theory, we obtained spatial maps of WM engagement which highlight WM regions critical for efficient communications across the brain. The distributions of WM engagement are highly reproducible across subjects and depict a notable interdependence between the distribution of GM activities and the detailed organization of WM. Additionally, we provide evidence that the engagement varies over time and shows significant differences between genders. These findings suggest the potential of WM engagement as a measure of the integrity of normal brain functions and as a biomarker for neurological and cognitive disorders.

Contrast-free dynamic susceptibility contrast using sinusoidal and bolus oxygenation challenges.

Deoxygenation-based dynamic susceptibility contrast (dDSC) MRI uses respiratory challenges as a source of endogenous contrast as an alternative to gadolinium injection. These gas challenges induce T2*-weighted MRI signal losses, after which tracer kinetics modeling was applied to calculate cerebral perfusion. This work compares three gas challenges, desaturation (transient hypoxia), resaturation (transient normoxia), and SineO2 (sinusoidal modulation of end-tidal oxygen pressures) in a cohort of 10 healthy volunteers (age 37 ± 11 years; 60% female). Perfusion estimates consisted of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). Calculations were computed using a traditional tracer kinetics model in the time domain for desaturation and resaturation and in the frequency domain for SineO2. High correlations and limits of agreement were observed among the three deoxygenation-based paradigms for CBV, although MTT and CBF estimates varied with the hypoxic stimulus. Cross-modality correlation with gadolinium DSC was lower, particularly for MTT, but on a par with agreement between the other perfusion references. Overall, this work demonstrated the feasibility and reliability of oxygen respiratory challenges to measure brain perfusion. Additional work is needed to assess the utility of dDSC in the diagnostic evaluation of various pathologies such as ischemic strokes, brain tumors, and neurodegenerative diseases.

Reductions in the white-gray functional connectome in preclinical Alzheimer's disease and their associations with amyloid and cognition.

BACKGROUND: The magnitudes and patterns of alterations of the white-gray matter (WM-GM) functional connectome in preclinical Alzheimer's disease (AD), and their associations with amyloid and cognition, remain unclear. METHODS: We compared regional WM-GM functional connectivity (FC) and network properties in subjects with preclinical AD (or AD dementia) and controls (total n = 344). Their associations with positron emission tomography AV45-measured amyloid beta (Aß) load and modified Preclinical Alzheimer Cognitive Composite (mPACC) scores were examined. RESULTS: Preclinical AD subjects showed lower FC in specific WM-GM pairs and reduced segregation of control, dorsal attention, and somatomotor networks. A major portion of the reduced FC and network segregations were linked to elevated Aß. Reduced FC of one WM-GM pair correlated with impaired mPACC. AD dementia exhibited broader reductions and stronger associations. DISCUSSION: The WM-GM functional connectome undergoes regional and systemic dysfunctions as early as in the preclinical stage, correlating with amyloid deposition and predicting cognitive impairment. HIGHLIGHTS: Preclinical Alzheimer's disease (AD) subjects showed lower functional connectivity in specific white-gray matter (WM-GM) pairs and reduced segregations of control, dorsal attention, and somatomotor networks. A major portion of the reduced connectivity and network segregations were linked to elevated amyloid beta load. Only one WM-GM pair's reduced connectivity was linearly correlated with impaired cognitive composite scores. AD dementia showed more extensive reductions in connectivity, network integration, and segregation, with stronger associations with amyloid elevation and cognitive impairment. The WM-GM functional connectome offers a distinct perspective for understanding changes in brain functional architecture throughout the AD continuum.

Characteristics of Physical Activity Interventions for People With Visual Impairments: A Scoping Review.

This study evaluated physical activity interventions designed for individuals with visual impairments and sought to guide health intervention scientists aiming to promote physical activity in this demographic. We delved into the specifics of participants' visual impairments, intervention features, accommodation approaches, and replicability prospects. The search spanned four databases, namely PubMed, CINAHL, SportDiscus, and Scopus, providing a wide scope and diversity of potential studies. There were no restrictions on publication years. We reviewed 13 studies, totaling 15 interventions. A consensus on visual-impairment definitions remains elusive, and the intervention dosages displayed variability. Notably, 66.7% (n = 7) integrated behavior-change techniques to amplify physical activity levels. Multiple studies employed audio descriptions as an accommodation method. While most studies provided adequate information for potential replication, detailed study protocols were frequently absent. It is essential for developed interventions to be persistently evaluated and fine-tuned to optimize results.

Personal Health Data Tracking by Blind and Low-Vision People: Survey Study.

BACKGROUND: Personal health technologies, including wearable tracking devices and mobile apps, have great potential to equip the general population with the ability to monitor and manage their health. However, being designed for sighted people, much of their functionality is largely inaccessible to the blind and low-vision (BLV) population, threatening the equitable access to personal health data (PHD) and health care services. OBJECTIVE: This study aims to understand why and how BLV people collect and use their PHD and the obstacles they face in doing so. Such knowledge can inform accessibility researchers and technology companies of the unique self-tracking needs and accessibility challenges that BLV people experience. METHODS: We conducted a web-based and phone survey with 156 BLV people. We reported on quantitative and qualitative findings regarding their PHD tracking practices, needs, accessibility barriers, and work-arounds. RESULTS: BLV respondents had strong desires and needs to track PHD, and many of them were already tracking their data despite many hurdles. Popular tracking items (ie, exercise, weight, sleep, and food) and the reasons for tracking were similar to those of sighted people. BLV people, however, face many accessibility challenges throughout all phases of self-tracking, from identifying tracking tools to reviewing data. The main barriers our respondents experienced included suboptimal tracking experiences and insufficient benefits against the extended burden for BLV people. CONCLUSIONS: We reported the findings that contribute to an in-depth understanding of BLV people's motivations for PHD tracking, tracking practices, challenges, and work-arounds. Our findings suggest that various accessibility challenges hinder BLV individuals from effectively gaining the benefits of self-tracking technologies. On the basis of the findings, we discussed design opportunities and research areas to focus on making PHD tracking technologies accessible for all, including BLV people.

Atypical lipomatous tumour/well-differentiated liposarcoma found in the buccal mucosa: A rare case report.

Oral liposarcomas are uncommon diseases, the most predominant histopathological subtype being atypical lipomatous tumour/well-differentiated liposarcoma. In regard to its clinical aspects in the oral cavity, it is challenging to confirm a diagnosis and develop a treatment plan. In this case report, we present a rare case of atypical lipomatous tumour/well-differentiated liposarcoma in the right cheek of a 77-year-old male patient. Conservative surgery was performed considering the histopathological subtype of the neoplasm. Knowledge of the clinical and histopathological characteristics of this rare disease is essential to maintaining function and aesthetics through conservative treatment in older patients.

Withaferin A mitigates metastatic traits in human oral squamous cell carcinoma caused by aberrant claudin-1 expression.

Abnormal expression of claudin-1 (CLDN1) has important roles in carcinogenesis and metastasis in various cancers. The role of CLDN1 in human oral squamous cell carcinoma (OSCC) remains unknown. Here, we report the functional role of CLDN1 in metastasis of human OSCC, as a potential target regulated by withaferin A. From gene expression profiling with microarray technology, we found that the majority of notable differentially expressed genes were classified into migration/invasion category. Withaferin A impaired the motility of human OSCC cells in vitro and suppressed metastatic nodule formation in an in vivo metastasis model, both associated with reduced CLDN1. CLDN1 overexpression enhanced metastatic nodule formation in vivo, resulting in severe metastatic lesions in lung tissue. Moreover, CLDN1 expression was positively correlated to lymphatic metastasis in OSCC patients. The impaired motility of human OSCC cells upon withaferin A treatment was restored by CLDN1 overexpression. Furthermore, upregulation of let-7a induced by withaferin A was inversely correlated to CLDN1 expression. Overall, these give us an insight into the function of CLDN1 for prognosis and treatment of human OSCC, substantiating further investigation into the use of withaferin A as good anti-metastatic drug candidate.

Anti-PTK7 Monoclonal Antibodies Exhibit Anti-Tumor Activity at the Cellular Level and in Mouse Xenograft Models of Esophageal Squamous Cell Carcinoma.

PTK7 is a catalytically defective receptor protein tyrosine kinase upregulated in various cancers, including esophageal squamous cell carcinoma (ESCC). In previous studies, we observed a positive correlation between PTK7 expression levels and tumorigenicity in various ESCC cell lines and xenograft mice with ESCC KYSE-30 cells. In this study, we analyzed the effects of anti-PTK7 monoclonal antibodies (mAbs) on the tumorigenic activity in KYSE-30 cells and in mouse xenograft models. PTK7 mAb-32 and mAb-43 bind with a high affinity to the extracellular domain of PTK7. PTK7 mAbs significantly reduced three-dimensional cell proliferation, adhesion, wound healing, and migration. PTK7 mAbs also reduce chemotactic invasiveness by decreasing MMP-9 secretion. PTK7 mAbs decreased actin cytoskeleton levels in the cortical region of KYSE-30 cells. PTK7 mAbs reduced the phosphorylation of ERK, SRC, and FAK. In a mouse xenograft model of ESCC using KYSE-30 cells, PTK7 mAbs reduced tumor growth in terms of volume, weight, and the number of Ki-67-positive cells. These results demonstrated that PTK7 mAbs can inhibit the tumorigenicity of ESCC at the cellular level and in vivo by blocking the function of PTK7. Considering the anticancer activities of PTK7 mAbs, we propose that PTK7 mAbs can be used in an effective treatment strategy for PTK7-positive malignancies, such as ESCC.

Management of Chronic Idiopathic Pain in Patients With Dental Implant Without a Clear Pathological Lesion: A Retrospective Study.

Non-nociceptive, persistent idiopathic facial pain (PIFP) is a poorly localized, continuous dull pain that occurs even in the absence of apparent pathological lesions or clinical neurologic deficiency. This study aimed to investigate the disease characteristics of PIFP that developed after dental implant treatment. The clinical characteristics of pain as well as treatment method and outcomes were retrospectively analyzed in 20 patients diagnosed with PIFP. The patients developed pain either after implant fixation or prosthetic treatment. In most patients, the pain persisted not only around the implant region but also at a distant site from the related implant (13/20, 65%). Many patients desired removal of the implants to manage the pain although the pain was not considered to be related to the implant treatment. In 12 patients, the related implants were removed, but 67% (n = 8/12) of the patients still experienced chronic pain after implant removal. Medication helped decrease the pain in most patients (n = 17). Pregabalin and clonazepam showed relatively higher efficiency than other medications for controlling the pain. The results showed that although the onset of PIFP was related to dental implant treatment, implant removal could not be considered a reliable option for the management of PIFP. Although medication controls the pain at least partially, complete pain control with medication should not be expected. These results demonstrate that an accurate diagnosis of PIFP is important for the selection of appropriate treatment.

Aspergillosis of the Maxillary Sinus Associated With Dental Implant.

Aspergillosis is a fungal disease caused by the fungus Aspergillus; this disease frequently involves the lungs and occasionally the maxillary sinus. Aspergillosis in the maxillary sinus usually has the characteristics of a noninvasive form. It has been suggested that spores of aspergillus can be inhaled into the maxillary sinus via the osteomeatal complex or via an oroantral fistula after dental procedures, such as an extraction. However, maxillary aspergillosis related to implant installation has rarely been reported. This report regards unusual cases of maxillary aspergillosis associated with dental implant therapies in healthy patients. The cases were successfully treated with the surgical removal of the infected or necrotic tissues.

Research topics in intellectual disabilities in North Korea: A scoping review.

BACKGROUND: Research outcomes on intellectual development and related disabilities in North Korea are not widely known. Therefore, the current scoping review aimed to provide preliminary insight on research topics concerning intellectual disabilities in North Korea. METHOD: A six-stage framework for scoping review was adopted to examine research trends. Articles were categorised based on the era of supreme leader and research topic. RESULTS: There is a greater amount of research regarding intellectual disabilities in the recent Kim Jong-un era compared to the period of the previous leader where research outcomes on general intelligence were the focus. Significant qualitative progress was similarly found. CONCLUSIONS: The current analysis on research outcomes provides meaningful insights to aid in understanding the atmosphere in North Korea surrounding intellectual disabilities. Follow-up studies and open discussions are necessary for further progress.

Calibration of T2 oximetry MRI for subjects with sickle cell disease.

PURPOSE: Cerebral T2 oximetry is a non-invasive imaging method to measure blood T2 and cerebral venous oxygenation. Measured T2 values are converted to oximetry estimates using carefully validated and potentially disease-specific calibrations. In sickle cell disease, red blood cells have abnormal cell shape and membrane properties that alter T2 oximetry calibration relationships in clinically meaningful ways. Previous in vitro works by two independent groups established potentially competing calibration models. METHODS: This study analyzed pooled datasets from these two studies to establish a unified and more robust sickle-specific calibration to serve as a reference standard in the field. RESULTS: Even though the combined calibration did not demonstrate statistical superiority compared to previous models, the calibration was unbiased compared to blood-gas co-oximetry and yielded limits of agreement of (-10.1%, 11.6%) in non-transfused subjects with sickle cell disease. In transfused patients, this study proposed a simple correction method based on individual hemoglobin S percentage that demonstrated reduced bias in saturation measurement compared to previous uncorrected sickle calibrations. CONCLUSION: The combined calibration is based on a larger range of hematocrit, providing greater confidence in the hematocrit-dependent model parameters, and yielded unbiased estimates to blood-gas co-oximetry measurements from both sites. Additionally, this work also demonstrated the need to correct for transfusion in T2 oximetry measurements for hyper-transfused sickle cell disease patients and proposes a correction method based on patient-specific hemoglobin S concentration.

miR-431 Promotes Metastasis of Pancreatic Neuroendocrine Tumors by Targeting DAB2 Interacting Protein, a Ras GTPase Activating Protein Tumor Suppressor.

The incidence of pancreatic neuroendocrine tumor (PNET) is increasing, and it presents with various clinical manifestations and an unfavorable survival rate. A better understanding of the drivers of PNET tumorigenesis is urgently needed. Distinct miRNA signatures have been identified for different stages of tumorigenesis in both human and mouse PNETs. The functions of these miRNAs are poorly understood. miR-431 is the most up-regulated miRNA in the metastatic signature. However, it is unknown whether miR-431 contributes to metastasis of PNETs. Herein, we show that miR-431 overexpression activates Ras/extracellular signal-regulated kinase (Erk) signaling and promotes epithelial-mesenchymal transition, migration/invasion in vitro, and metastasis in both xenograft and spontaneous mouse models of PNET. Treatment of PNET cells with Erk inhibitor or locked nucleic acids sequestering miR-431 inhibits invasion. Four target prediction modules and dual-luciferase reporter assays were used to identify potential mRNA targets of miR-431. A Ras GTPase activating protein tumor suppressor (RasGAP), DAB2 interacting protein (DAB2IP), was discovered as an miR-431 target. Overexpression of DAB2IP's rat homolog, but not its mutant defective in Ras GTPase activating protein activity, reverses miR-431's effect on promoting invasion, Erk phosphorylation, and epithelial-mesenchymal transition of PNETs. Taken together, miR-431 silences DAB2IP to active Ras/Erk and promote metastasis of PNETs. miR-431 may be targeted to manage metastatic PNETs.

Reduced global cerebral oxygen metabolic rate in sickle cell disease and chronic anemias.

Anemia is the most common blood disorder in the world. In patients with chronic anemia, such as sickle cell disease or major thalassemia, cerebral blood flow increases to compensate for decreased oxygen content. However, the effects of chronic anemia on oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) are less well understood. In this study, we examined 47 sickle-cell anemia subjects (age 21.7 ± 7.1, female 45%), 27 non-sickle anemic subjects (age 25.0 ± 10.4, female 52%) and 44 healthy controls (age 26.4 ± 10.6, female 71%) using MRI metrics of brain oxygenation and flow. Phase contrast MRI was used to measure resting cerebral blood flow, while T2 -relaxation-under-spin-tagging (TRUST) MRI with disease appropriate calibrations were used to measure OEF and CMRO2 . We observed that patients with sickle cell disease and other chronic anemias have decreased OEF and CMRO2 (respectively 27.4 ± 4.1% and 3.39 ± 0.71 ml O2 /100 g/min in sickle cell disease, 30.8 ± 5.2% and 3.53 ± 0.64 ml O2 /100 g/min in other anemias) compared to controls (36.7 ± 6.0% and 4.00 ± 0.65 ml O2 /100 g/min). Impaired CMRO2 was proportional to the degree of anemia severity. We further demonstrate striking concordance of the present work with pooled historical data from patients having broad etiologies for their anemia. The reduced cerebral oxygen extraction and metabolism are consistent with emerging data demonstrating increased non-nutritive flow, or physiological shunting, in sickle cell disease patients.

Resveratrol enhances bone formation by modulating inflammation in the mouse periodontitis model.

OBJECTIVE: To evaluate the effect of resveratrol on periodontal bone regeneration after local delivery and to determine its effect on inflammatory mediators. BACKGROUND: Resveratrol is considered an anti-inflammatory polyphenolic stilbene involved in the modulation of inflammation. MATERIALS AND METHODS: Periodontitis was induced in mouse molars using a 5-day ligature model followed by the left second molar extraction and 50 µM resveratrol treatment for 1 and 2 weeks. We then examined specimens treated for 1 week histologically and with immunostaining. Microfocus-computed tomography (micro-CT) was used to examine the bone volume formation. RESULTS: After 1 week of treatment, proinflammatory cytokine levels (TNF-alpha and IL6), cells exhibiting neutrophil and macrophage marker (MPO), cell proliferation marker (Ki67), and preosteoblastic marker (RUNX2) reactivity decreased in the resveratrol-treated specimens compared to the control group. In contrast, we observed a higher number of CD31-, F4/80-, and osteocalcin- (OCN-) positive cells in the resveratrol-treated specimens. After 2 weeks, micro-CT confirmed an increased bone mass in the region of the extraction socket in the resveratrol-treated group. CONCLUSION: After 1 week, the resveratrol-treated specimens revealed evidence of inflammation modulation compared to the control group. These data suggest that resveratrol not only affects inflammation control but also is useful for treating periodontitis-related tissue defects and bone regeneration.

Global Lysine Acetylome Analysis of LPS-Stimulated HepG2 Cells Identified Hyperacetylation of PKM2 as a Metabolic Regulator in Sepsis.

Sepsis-induced liver dysfunction (SILD) is a common event and is strongly associated with mortality. Establishing a causative link between protein post-translational modification and diseases is challenging. We studied the relationship among lysine acetylation (Kac), sirtuin (SIRTs), and the factors involved in SILD, which was induced in LPS-stimulated HepG2 cells. Protein hyperacetylation was observed according to SIRTs reduction after LPS treatment for 24 h. We identified 1449 Kac sites based on comparative acetylome analysis and quantified 1086 Kac sites on 410 proteins for acetylation. Interestingly, the upregulated Kac proteins are enriched in glycolysis/gluconeogenesis pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) category. Among the proteins in the glycolysis pathway, hyperacetylation, a key regulator of lactate level in sepsis, was observed at three pyruvate kinase M2 (PKM2) sites. Hyperacetylation of PKM2 induced an increase in its activity, consequently increasing the lactate concentration. In conclusion, this study is the first to conduct global profiling of Kac, suggesting that the Kac mechanism of PKM2 in glycolysis is associated with sepsis. Moreover, it helps to further understand the systematic information regarding hyperacetylation during the sepsis process.

Differential Angiogenic Potential of 3-Dimension Spheroid of HNSCC Cells in Mouse Xenograft.

The experimental animal model is still essential in the development of new anticancer drugs. We characterized mouse tumors derived from two-dimensional (2D) monolayer cells or three-dimensional (3D) spheroids to establish an in vivo model with highly standardized conditions. Primary cancer-associated fibroblasts (CAFs) were cultured from head and neck squamous cell carcinoma (HNSCC) tumor tissues and co-injected with monolayer cancer cells or spheroids into the oral mucosa of mice. Mice tumor blood vessels were stained, followed by tissue clearing and 3D Lightsheet fluorescent imaging. We compared the effect of exosomes secreted from 2D or 3D culture conditions on the angiogenesis-related genes in HNSCC cells. Our results showed that both the cells and spheroids co-injected with primary CAFs formed tumors. Interestingly, vasculature was abundantly distributed inside the spheroid-derived but not the monolayer-derived mice tumors. In addition, cisplatin injection more significantly decreased spheroid-derived but not monolayer-derived tumor size in mice. Additionally, exosomes isolated from co-culture media of FaDu spheroid and CAF upregulated angiogenesis-related genes in HNSCC cells as compared to exosomes from FaDu cell and CAF co-culture media under in vitro conditions. The mouse tumor xenograft model derived from 3D spheroids of HNSCC cells with primary CAFs is expected to produce reliable chemotherapy drug screening results given the robust angiogenesis and lack of necrosis inside tumor tissues.

Transient Hypoxia Model Revealed Cerebrovascular Impairment in Anemia Using BOLD MRI and Near-Infrared Spectroscopy.

BACKGROUND: Obstructive sleep apnea and nocturnal oxygen desaturations, which are prevalent in sickle cell disease (SCD) and chronic anemia disorders, have been linked to risks of stroke and silent cerebral infarcts (SCI). Cerebrovascular response to intermittent desaturations has not been well studied and may identify patients at greatest risk. PURPOSE: To investigate the cerebral dynamic response to induced desaturation in SCD patients with and without SCI, chronic anemia, and healthy subjects. STUDY TYPE: Prospective. SUBJECTS: Twenty-six SCD patients (age = 21 ± 8.2, female 46.2%), including 15 subjects without SCI and nine subjects with SCI, 15 nonsickle anemic patients (age = 22 ± 5.8, female 66.7%), and 31 controls (age = 28 ± 12.3, female 77.4%). FIELD STRENGTH/SEQUENCE: 3T, gradient-echo echo-planar imaging. ASSESSMENT: A transient hypoxia challenge of five breaths of 100% nitrogen gas was performed with blood oxygen level-dependent (BOLD) MRI and near-infrared spectroscopy (NIRS) acquisitions. Hypoxia responses were characterized by desaturation depth, time-to-peak, return-to-baseline half-life, and posthypoxia recovery in the BOLD and NIRS time courses. SCI were documented by T2 fluid-attenuation inversion recovery (FLAIR). STATISTICAL TESTS: Univariate and multivariate regressions were performed between hypoxic parameters and anemia predictors. Voxelwise two-sample t-statistic maps were used to assess the regional difference in hypoxic responses between anemic and control groups. RESULTS: Compared to controls, SCD and chronically anemic patients demonstrated significantly higher desaturation depth (P < 0.01) and shorter return-to-baseline timing response (P < 0.01). Patients having SCI had shorter time-to-peak (P < 0.01), return-to-baseline (P < 0.01), and larger desaturation depth (P < 0.01) in both white matter regions at risk and normal-appearing white matter than patients without infarcts. On multivariate analysis, desaturation depth and timing varied with age, sex, blood flow, white blood cells, and cell-free hemoglobin (r2 = 0.25 for desaturation depth; r2 = 0.18 for time-to-peak; r2 = 0.37 for return-to-baseline). DATA CONCLUSION: Transient hypoxia revealed global and regional response differences between anemic and healthy subjects. SCI was associated with extensive heterogeneity of desaturation dynamics, consistent with extensive underlying microvascular remodeling.