Automated Quality Evaluation Index for Arterial Spin Labeling Derived Cerebral Blood Flow Maps.

BACKGROUND: Arterial spin labeling (ASL) derived cerebral blood flow (CBF) maps are prone to artifacts and noise that can degrade image quality. PURPOSE: To develop an automated and objective quality evaluation index (QEI) for ASL CBF maps. STUDY TYPE: Retrospective. POPULATION: Data from N = 221 adults, including patients with Alzheimer's disease (AD), Parkinson's disease, and traumatic brain injury. FIELD STRENGTH/SEQUENCE: Pulsed or pseudocontinuous ASL acquired at 3 T using non-background suppressed 2D gradient-echo echoplanar imaging or background suppressed 3D spiral spin-echo readouts. ASSESSMENT: The QEI was developed using N = 101 2D CBF maps rated as unacceptable, poor, average, or excellent by two neuroradiologists and validated by 1) leave-one-out cross validation, 2) assessing if CBF reproducibility in N = 53 cognitively normal adults correlates inversely with QEI, 3) if iterative discarding of low QEI data improves the Cohen's d effect size for CBF differences between preclinical AD (N = 27) and controls (N = 53), 4) comparing the QEI with manual ratings for N = 50 3D CBF maps, and 5) comparing the QEI with another automated quality metric. STATISTICAL TESTS: Inter-rater reliability and manual vs. automated QEI were quantified using Pearson's correlation. P < 0.05 was considered significant. RESULTS: The correlation between QEI and manual ratings (R = 0.83, CI: 0.76-0.88) was similar (P = 0.56) to inter-rater correlation (R = 0.81, CI: 0.73-0.87) for the 2D data. CBF reproducibility correlated negatively (R = -0.74, CI: -0.84 to -0.59) with QEI. The effect size comparing patients and controls improved (R = 0.72, CI: 0.59-0.82) as low QEI data was discarded iteratively. The correlation between QEI and manual ratings (R = 0.86, CI: 0.77-0.92) of 3D ASL was similar (P = 0.09) to inter-rater correlation (R = 0.78, CI: 0.64-0.87). The QEI correlated (R = 0.87, CI: 0.77-0.92) significantly better with manual ratings than did an existing approach (R = 0.54, CI: 0.30-0.72). DATA CONCLUSION: Automated QEI performed similarly to manual ratings and can provide scalable ASL quality control. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Impact of white matter hyperintensities on structural connectivity and cognition in cognitively intact ADNI participants.

We used indirect brain mapping with virtual lesion tractography to test the hypothesis that the extent of white matter tract disconnection due to white matter hyperintensities (WMH) is associated with corresponding tract-specific cognitive performance decrements. To estimate tract disconnection, WMH masks were extracted from FLAIR MRI data of 481 cognitively intact participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and used as regions of avoidance for fiber tracking in diffusion MRI data from 50 healthy young participants from the Human Connectome Project. Estimated tract disconnection in the right inferior fronto-occipital fasciculus, right frontal aslant tract, and right superior longitudinal fasciculus mediated the effects of WMH volume on executive function. Estimated tract disconnection in the left uncinate fasciculus mediated the effects of WMH volume on memory and in the right frontal aslant tract on language. In a subset of ADNI control participants with amyloid data, positive status increased the probability of periventricular WMH and moderated the relationship between WMH burden and tract disconnection in executive function performance.

ASL lexicon and reporting recommendations: A consensus report from the ISMRM Open Science Initiative for Perfusion Imaging (OSIPI).

The 2015 consensus statement published by the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group and the European Cooperation in Science and Technology ( COST) Action ASL in Dementia aimed to encourage the implementation of robust arterial spin labeling (ASL) perfusion MRI for clinical applications and promote consistency across scanner types, sites, and studies. Subsequently, the recommended 3D pseudo-continuous ASL sequence has been implemented by most major MRI manufacturers. However, ASL remains a rapidly and widely developing field, leading inevitably to further divergence of the technique and its associated terminology, which could cause confusion and hamper research reproducibility. On behalf of the ISMRM Perfusion Study Group, and as part of the ISMRM Open Science Initiative for Perfusion Imaging (OSIPI), the ASL Lexicon Task Force has been working on the development of an ASL Lexicon and Reporting Recommendations for perfusion imaging and analysis, aiming to (1) develop standardized, consensus nomenclature and terminology for the broad range of ASL imaging techniques and parameters, as well as for the physiological constants required for quantitative analysis; and (2) provide a community-endorsed recommendation of the imaging parameters that we encourage authors to include when describing ASL methods in scientific reports/papers. In this paper, the sequences and parameters in (pseudo-)continuous ASL, pulsed ASL, velocity-selective ASL, and multi-timepoint ASL for brain perfusion imaging are included. However, the content of the lexicon is not intended to be limited to these techniques, and this paper provides the foundation for a growing online inventory that will be extended by the community as further methods and improvements are developed and established.

ISMRM Open Science Initiative for Perfusion Imaging (OSIPI): ASL pipeline inventory.

PURPOSE: To create an inventory of image processing pipelines of arterial spin labeling (ASL) and list their main features, and to evaluate the capability, flexibility, and ease of use of publicly available pipelines to guide novice ASL users in selecting their optimal pipeline. METHODS: Developers self-assessed their pipelines using a questionnaire developed by the Task Force 1.1 of the ISMRM Open Science Initiative for Perfusion Imaging. Additionally, each publicly available pipeline was evaluated by two independent testers with basic ASL experience using a scoring system created for this purpose. RESULTS: The developers of 21 pipelines filled the questionnaire. Most pipelines are free for noncommercial use (n = 18) and work with the standard NIfTI (Neuroimaging Informatics Technology Initiative) data format (n = 15). All pipelines can process standard 3D single postlabeling delay pseudo-continuous ASL images and primarily differ in their support of advanced sequences and features. The publicly available pipelines (n = 9) were included in the independent testing, all of them being free for noncommercial use. The pipelines, in general, provided a trade-off between ease of use and flexibility for configuring advanced processing options. CONCLUSION: Although most ASL pipelines can process the common ASL data types, only some (namely, ASLPrep, ASLtbx, BASIL/Quantiphyse, ExploreASL, and MRICloud) are well-documented, publicly available, support multiple ASL types, have a user-friendly interface, and can provide a useful starting point for ASL processing. The choice of an optimal pipeline should be driven by specific data to be processed and user experience, and can be guided by the information provided in this ASL inventory.

Young versus older subject diffusion magnetic resonance imaging data for virtual white matter lesion tractography.

White matter hyperintensity (WMH) lesions on T2 fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) and changes in adjacent normal-appearing white matter can disrupt computerized tract reconstruction and result in inaccurate measures of structural brain connectivity. The virtual lesion approach provides an alternative strategy for estimating structural connectivity changes due to WMH. To assess the impact of using young versus older subject diffusion MRI data for virtual lesion tractography, we leveraged recently available diffusion MRI data from the Human Connectome Project (HCP) Lifespan database. Neuroimaging data from 50 healthy young (39.2 ± 1.6 years) and 46 healthy older (74.2 ± 2.5 years) subjects were obtained from the publicly available HCP-Aging database. Three WMH masks with low, moderate, and high lesion burdens were extracted from the WMH lesion frequency map of locally acquired FLAIR MRI data. Deterministic tractography was conducted to extract streamlines in 21 WM bundles with and without the WMH masks as regions of avoidance in both young and older cohorts. For intact tractography without virtual lesion masks, 7 out of 21 WM pathways showed a significantly lower number of streamlines in older subjects compared to young subjects. A decrease in streamline count with higher native lesion burden was found in corpus callosum, corticostriatal tract, and fornix pathways. Comparable percentages of affected streamlines were obtained in young and older groups with virtual lesion tractography using the three WMH lesion masks of increasing severity. We conclude that using normative diffusion MRI data from young subjects for virtual lesion tractography of WMH is, in most cases, preferable to using age-matched normative data.

Association of Intensive vs Standard Blood Pressure Control With Regional Changes in Cerebral Small Vessel Disease Biomarkers: Post Hoc Secondary Analysis of the SPRINT MIND Randomized Clinical Trial.

Importance: Little is known about the associations of strict blood pressure (BP) control with microstructural changes in small vessel disease markers. Objective: To investigate the regional associations of intensive vs standard BP control with small vessel disease biomarkers, such as white matter lesions (WMLs), fractional anisotropy (FA), mean diffusivity (MD), and cerebral blood flow (CBF). Design, Setting, and Participants: The Systolic Blood Pressure Intervention Trial (SPRINT) is a multicenter randomized clinical trial that compared intensive systolic BP (SBP) control (SBP target <120 mm Hg) vs standard control (SBP target <140 mm Hg) among participants aged 50 years or older with hypertension and without diabetes or a history of stroke. The study began randomization on November 8, 2010, and stopped July 1, 2016, with a follow-up duration of approximately 4 years. A total of 670 and 458 participants completed brain magnetic resonance imaging at baseline and follow-up, respectively, and comprise the cohort for this post hoc analysis. Statistical analyses for this post hoc analysis were performed between August 2020 and October 2022. Interventions: At baseline, 355 participants received intensive SBP treatment and 315 participants received standard SBP treatment. Main Outcomes and Measures: The main outcomes were regional changes in WMLs, FA, MD (in white matter regions of interest), and CBF (in gray matter regions of interest). Results: At baseline, 355 participants (mean [SD] age, 67.7 [8.0] years; 200 men [56.3%]) received intensive BP treatment and 315 participants (mean [SD] age, 67.0 [8.4] years; 199 men [63.2%]) received standard BP treatment. Intensive treatment was associated with smaller mean increases in WML volume compared with standard treatment (644.5 mm3 vs 1258.1 mm3). The smaller mean increases were observed specifically in the deep white matter regions of the left anterior corona radiata (intensive treatment, 30.3 mm3 [95% CI, 16.0-44.5 mm3]; standard treatment, 80.5 mm3 [95% CI, 53.8-107.2 mm3]), left tapetum (intensive treatment, 11.8 mm3 [95% CI, 4.4-19.2 mm3]; standard treatment, 27.2 mm3 [95% CI, 19.4-35.0 mm3]), left superior fronto-occipital fasciculus (intensive treatment, 3.2 mm3 [95% CI, 0.7-5.8 mm3]; standard treatment, 9.4 mm3 [95% CI, 5.5-13.4 mm3]), left posterior corona radiata (intensive treatment, 26.0 mm3 [95% CI, 12.9-39.1 mm3]; standard treatment, 52.3 mm3 [95% CI, 34.8-69.8 mm3]), left splenium of the corpus callosum (intensive treatment, 45.4 mm3 [95% CI, 25.1-65.7 mm3]; standard treatment, 83.0 mm3 [95% CI, 58.7-107.2 mm3]), left posterior thalamic radiation (intensive treatment, 53.0 mm3 [95% CI, 29.8-76.2 mm3]; standard treatment, 106.9 mm3 [95% CI, 73.4-140.3 mm3]), and right posterior thalamic radiation (intensive treatment, 49.5 mm3 [95% CI, 24.3-74.7 mm3]; standard treatment, 102.6 mm3 [95% CI, 71.0-134.2 mm3]). Conclusions and Relevance: This study suggests that intensive BP treatment, compared with standard treatment, was associated with a slower increase of WMLs, improved diffusion tensor imaging, and FA and CBF changes in several brain regions that represent vulnerable areas that may benefit from more strict BP control. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

Temporal dynamics of cerebral blood flow during the first year after moderate-severe traumatic brain injury: A longitudinal perfusion MRI study.

Traumatic brain injury (TBI) is associated with alterations in cerebral blood flow (CBF), which may underlie functional disability and precipitate TBI-induced neurodegeneration. Although it is known that chronic moderate-severe TBI (msTBI) causes decreases in CBF, the temporal dynamics during the early chronic phase of TBI remain unknown. Using arterial spin labeled (ASL) perfusion magnetic resonance imaging (MRI), we examined longitudinal CBF changes in 29 patients with msTBI at 3, 6, and 12 months post-injury in comparison to 35 demographically-matched healthy controls (HC). We investigated the difference between the two groups and the within-subject time effect in the TBI patients using whole-brain voxel-wise analysis. Mean CBF in gray matter (GM) was lower in the TBI group compared to HC at 6 and 12 months post-injury. Within the TBI group, we identified widespread regional decreases in CBF from 3 to 6 months post-injury. In contrast, there were no regions with decreasing CBF from 6 to 12 months post-injury, indicating stabilization of hypoperfusion. There was instead a small area of increase in CBF observed in the right precuneus. These CBF changes were not accompanied by cortical atrophy. The change in CBF was correlated with change in executive function from 3 to 6 months post-injury in TBI patients, suggesting functional relevance of CBF measures. Understanding the time course of TBI-induced hypoperfusion and its relationship with cognitive improvement could provide an optimal treatment window to benefit long-term outcome.

Association of Cerebral Blood Flow With Longitudinal Changes in Cerebral Microstructural Integrity in the Coronary Artery Risk Development in Young Adults (CARDIA) Study.

Importance: Decreased cerebral tissue integrity and cerebral blood flow (CBF) are features of neurodegenerative diseases. Brain tissue maintenance is an energy-demanding process, making it particularly sensitive to hypoperfusion. However, little is known about the association between blood flow and brain microstructural integrity, including in normative aging. Objective: To assess associations between CBF and changes in cerebral tissue integrity in white matter and gray matter brain regions. Design, Setting, and Participants: In this longitudinal cohort study, magnetic resonance imaging was performed on 732 healthy adults from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a prospective longitudinal study (baseline age of 18-30 years) that examined participants up to 8 times during 30 years (1985-1986 to 2015-2016). Cerebral blood flow was measured at baseline (year 25 of the CARDIA study), and changes in diffusion tensor indices of fractional anisotropy (FA) and mean diffusivity (MD), measures of microstructural tissue integrity, were measured at both baseline and after approximately 5 years of follow-up (year 30). Analyses were conducted from November 5, 2020, to January 29, 2022. Main Outcomes and Measures: Automated algorithms and linear mixed-effects statistical models were used to evaluate the associations between CBF at baseline and changes in FA or MD. Results: After exclusion of participants with missing or low-quality data, 654 at baseline (342 women; mean [SD] age, 50.3 [3.5] years) and 433 at follow-up (230 women; mean [SD] age, 55.1 [3.5] years) were scanned for CBF or FA and MD imaging. In the baseline cohort, 247 participants were Black (37.8%) and 394 were White (60.2%); in the follow-up cohort, 156 were Black (36.0%) and 277 were White (64.0%). Cross-sectionally, FA and MD were associated with CBF in most regions evaluated, with lower CBF values associated with lower FA or higher MD values, including the frontal white matter lobes (for CBF and MD: mean [SE] ß = -1.4 [0.5] × 10-6; for CBF and FA: mean [SE] ß = 2.9 [1.0] × 10-4) and the parietal white matter lobes (for CBF and MD: mean [SE] ß = -2.4 [0.6] × 10-6; for CBF and FA: mean [SE] ß = 4.4 [1.1] × 10-4). Lower CBF values at baseline were also significantly associated with steeper regional decreases in FA or increases in MD in most brain regions investigated, including the frontal (for CBF and MD: mean [SE] ß = -1.1 [0.6] × 10-6; for CBF and FA: mean [SE] ß = 2.9 [1.0] × 10-4) and parietal lobes (for CBF and MD: mean [SE] ß = -1.5 [0.7] × 10-6; for CBF and FA: mean [SE] ß = 4.4 [1.1] × 10-4). Conclusions and Relevance: Results of this longitudinal cohort study of the association between CBF and diffusion tensor imaging metrics suggest that blood flow may be significantly associated with brain tissue microstructure. This work may lay the foundation for investigations to clarify the nature of early brain damage in neurodegeneration. Such studies may lead to new neuroimaging biomarkers of brain microstructure and function for disease progression.

ASLPrep: a platform for processing of arterial spin labeled MRI and quantification of regional brain perfusion.

Arterial spin labeled (ASL) magnetic resonance imaging (MRI) is the primary method for noninvasively measuring regional brain perfusion in humans. We introduce ASLPrep, a suite of software pipelines that ensure the reproducible and generalizable processing of ASL MRI data.

Associations of white matter hyperintensities with networks of gray matter blood flow and volume in midlife adults: A coronary artery risk development in young adults magnetic resonance imaging substudy.

White matter hyperintensities (WMHs) are emblematic of cerebral small vessel disease, yet effects on the brain have not been well characterized at midlife. Here, we investigated whether WMH volume is associated with brain network alterations in midlife adults. Two hundred and fifty-four participants from the Coronary Artery Risk Development in Young Adults study were selected and stratified by WMH burden into Lo-WMH (mean age = 50 ± 3.5 years) and Hi-WMH (mean age = 51 ± 3.7 years) groups of equal size. We constructed group-level covariance networks based on cerebral blood flow (CBF) and gray matter volume (GMV) maps across 74 gray matter regions. Through consensus clustering, we found that both CBF and GMV covariance networks partitioned into modules that were largely consistent between groups. Next, CBF and GMV covariance network topologies were compared between Lo- and Hi-WMH groups at global (clustering coefficient, characteristic path length, global efficiency) and regional (degree, betweenness centrality, local efficiency) levels. At the global level, there were no between-group differences in either CBF or GMV covariance networks. In contrast, we found between-group differences in the regional degree, betweenness centrality, and local efficiency of several brain regions in both CBF and GMV covariance networks. Overall, CBF and GMV covariance analyses provide evidence that WMH-related network alterations are present at midlife.

Association of Intensive vs Standard Blood Pressure Control With Cerebral Blood Flow: Secondary Analysis of the SPRINT MIND Randomized Clinical Trial.

IMPORTANCE: Antihypertensive treatments benefit cerebrovascular health and cognitive function in patients with hypertension, but it is uncertain whether an intensive blood pressure target leads to potentially harmful cerebral hypoperfusion. OBJECTIVE: To investigate the association of intensive systolic blood pressure (SBP) control vs standard control with whole-brain cerebral blood flow (CBF). DESIGN, SETTING, AND PARTICIPANTS: This substudy of the Systolic Blood Pressure Intervention Trial (SPRINT) randomized clinical trial compared the efficacy of 2 different blood pressure-lowering strategies with longitudinal brain magnetic resonance imaging (MRI) including arterial spin labeled perfusion imaging to quantify CBF. A total of 1267 adults 50 years or older with hypertension and increased cardiovascular risk but free of diabetes or dementia were screened for the SPRINT substudy from 6 sites in the US. Randomization began in November 2010 with final follow-up MRI in July 2016. Analyses were performed from September 2020 through December 2021. INTERVENTIONS: Study participants with baseline CBF measures were randomized to an intensive SBP target less than 120 mm Hg or standard SBP target less than 140 mm Hg. MAIN OUTCOMES AND MEASURES: The primary outcome was change in whole-brain CBF from baseline. Secondary outcomes were change in gray matter, white matter, and periventricular white matter CBF. RESULTS: Among 547 participants with CBF measured at baseline, the mean (SD) age was 67.5 (8.1) years and 219 (40.0%) were women; 315 completed follow-up MRI at a median (IQR) of 4.0 (3.7-4.1) years after randomization. Mean whole-brain CBF increased from 38.90 to 40.36 (difference, 1.46 [95% CI, 0.08-2.83]) mL/100 g/min in the intensive treatment group, with no mean increase in the standard treatment group (37.96 to 37.12; difference, -0.84 [95% CI, -2.30 to 0.61] mL/100 g/min; between-group difference, 2.30 [95% CI, 0.30-4.30; P = .02]). Gray, white, and periventricular white matter CBF showed similar changes. The association of intensive vs standard treatment with CBF was generally similar across subgroups defined by age, sex, race, chronic kidney disease, SBP, orthostatic hypotension, and frailty, with the exception of an indication of larger mean increases in CBF associated with intensive treatment among participants with a history of cardiovascular disease (interaction P = .05). CONCLUSIONS AND RELEVANCE: Intensive vs standard antihypertensive treatment was associated with increased, rather than decreased, cerebral perfusion, most notably in participants with a history of cardiovascular disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01206062.

Race, sex, and mid-life changes in brain health: Cardia MRI substudy.

OBJECTIVE: To examine longitudinal race and sex differences in mid-life brain health and to evaluate whether cardiovascular health (CVH) or apolipoprotein E (APOE) ε4 explain differences. METHODS: The study included 478 Black and White participants (mean age: 50 years). Total (TBV), gray (GMV), white (WMV), and white matter hyperintensity (WMH) volumes and GM-cerebral blood flow (CBF) were acquired with 3T-magnetic resonance imaging at baseline and 5-year follow-up. Analyses were based on general linear models. RESULTS: There were race x sex interactions for GMV (P-interaction = .004) and CBF (P-interaction = .01) such that men showed more decline than women, and this was most evident in Blacks. Blacks compared to Whites had a significantly greater increase in WMH (P = .002). All sex-race differences in change were marginally attenuated by CVH and APOE ε4. CONCLUSION: Race-sex differences in brain health emerge by mid-life. Identifying new environmental factors beyond CVH is needed to develop early interventions to maintain brain health.

A Beginner's Guide to Arterial Spin Labeling (ASL) Image Processing.

Arterial spin labeling (ASL) is a non-invasive and cost-effective MRI technique for brain perfusion measurements. While it has developed into a robust technique for scientific and clinical use, its image processing can still be daunting. The 2019 Ann Arbor ISMRM ASL working group established that education is one of the main areas that can accelerate the use of ASL in research and clinical practice. Specifically, the post-acquisition processing of ASL images and their preparation for region-of-interest or voxel-wise statistical analyses is a topic that has not yet received much educational attention. This educational review is aimed at those with an interest in ASL image processing and analysis. We provide summaries of all typical ASL processing steps on both single-subject and group levels. The readers are assumed to have a basic understanding of cerebral perfusion (patho) physiology; a basic level of programming or image analysis is not required. Starting with an introduction of the physiology and MRI technique behind ASL, and how they interact with the image processing, we present an overview of processing pipelines and explain the specific ASL processing steps. Example video and image illustrations of ASL studies of different cases, as well as model calculations, help the reader develop an understanding of which processing steps to check for their own analyses. Some of the educational content can be extrapolated to the processing of other MRI data. We anticipate that this educational review will help accelerate the application of ASL MRI for clinical brain research.

Kidney Disease, Hypertension Treatment, and Cerebral Perfusion and Structure.

RATIONALE & OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in individuals with and without CKD. STUDY DESIGN: Neuroimaging substudy of a randomized trial. SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial (SPRINT) who underwent brain magnetic resonance imaging studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR). INTERVENTION: Participants were randomly assigned to intensive (systolic BP <120 mm Hg) versus standard (systolic BP <140 mm Hg) BP lowering. OUTCOMES: The magnetic resonance imaging outcome measures were the 4-year change in global cerebral blood flow (CBF), white matter lesion (WML) volume, and total brain volume (TBV). RESULTS: A total of 716 randomized participants with a mean age of 68 years were enrolled; follow-up imaging occurred after a median 3.9 years. Among participants with eGFR <60 mL/min/1.73 m2 (n = 234), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 3.38 (95% CI, 0.32 to 6.44) mL/100 g/min, -0.06 (95% CI, -0.16 to 0.04) cm3 (inverse hyperbolic sine-transformed), and -3.8 (95% CI, -8.3 to 0.7) cm3, respectively. Among participants with UACR >30 mg/g (n = 151), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 1.91 (95% CI, -3.01 to 6.82) mL/100 g/min, 0.003 (95% CI, -0.13 to 0.13) cm3 (inverse hyperbolic sine-transformed), and -7.0 (95% CI, -13.3 to -0.3) cm3, respectively. The overall treatment effects on CBF and TBV were not modified by baseline eGFR or UACR; however, the effect on WMLs was attenuated in participants with albuminuria (P = 0.04 for interaction). LIMITATIONS: Measurement variability due to multisite design. CONCLUSIONS: Among adults with hypertension who have primarily early kidney disease, intensive versus standard BP treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive BP treatment targets on brain health in persons with early kidney disease. FUNDING: SPRINT was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Aging; and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with study number NCT01206062.

Association of Intensive vs Standard Blood Pressure Control With Magnetic Resonance Imaging Biomarkers of Alzheimer Disease: Secondary Analysis of the SPRINT MIND Randomized Trial.

Importance: Meta-analyses of randomized clinical trials have indicated that improved hypertension control reduces the risk for cognitive impairment and dementia. However, it is unclear to what extent pathways reflective of Alzheimer disease (AD) pathology are affected by hypertension control. Objective: To evaluate the association of intensive blood pressure control on AD-related brain biomarkers. Design, Setting, and Participants: This is a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT MIND), a multicenter randomized clinical trial that compared the efficacy of 2 different blood pressure-lowering strategies. Potential participants (n = 1267) 50 years or older with hypertension and without a history of diabetes or stroke were approached for a brain magnetic resonance imaging (MRI) study. Of these, 205 participants were deemed ineligible and 269 did not agree to participate; 673 and 454 participants completed brain MRI at baseline and at 4-year follow-up, respectively; the final follow-up date was July 1, 2016. Analysis began September 2019 and ended November 2020. Interventions: Participants were randomized to either a systolic blood pressure goal of less than 120 mm Hg (intensive treatment: n = 356) or less than 140 mm Hg (standard treatment: n = 317). Main Outcomes and Measures: Changes in hippocampal volume, measures of AD regional atrophy, posterior cingulate cerebral blood flow, and mean fractional anisotropy in the cingulum bundle. Results: Among 673 recruited patients who had baseline MRI (mean [SD] age, 67.3 [8.2] years; 271 women [40.3%]), 454 completed the follow-up MRI at a median (interquartile range) of 3.98 (3.7-4.1) years after randomization. In the intensive treatment group, mean hippocampal volume decreased from 7.45 cm3 to 7.39 cm3 (difference, -0.06 cm3; 95% CI, -0.08 to -0.04) vs a decrease from 7.48 cm3 to 7.46 cm3 (difference, -0.02 cm3; 95% CI, -0.05 to -0.003) in the standard treatment group (between-group difference in change, -0.033 cm3; 95% CI, -0.062 to -0.003; P = .03). There were no significant treatment group differences for measures of AD regional atrophy, cerebral blood flow, or mean fractional anisotropy. Conclusions and Relevance: Intensive treatment was associated with a small but statistically significant greater decrease in hippocampal volume compared with standard treatment, consistent with the observation that intensive treatment is associated with greater decreases in total brain volume. However, intensive treatment was not associated with changes in any of the other MRI biomarkers of AD compared with standard treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

An MRI protocol for anatomical and functional evaluation of the California sea lion brain.

BACKGROUND: Domoic acid (DOM) is a neurotoxin produced by some harmful algae blooms in coastal waters. California sea lions (Zalophus californianus) exposed to DOM often strand on beaches where they exhibit a variety of symptoms, including seizures. These animals typically show hippocampal atrophy on MRI scans. NEW METHOD: We describe an MRI protocol for comprehensive evaluation of DOM toxicosis in the sea lion brain. We intend to study brain development in pups exposed in utero. The protocol depicts the hippocampal formation as the primary region of interest. We include scans for quantitative morphometry, functional and structural connectivity, and a cerebral blood flow map. RESULTS: High-resolution 3D anatomical scans facilitate post hoc slicing in arbitrary planes and accurate morphometry. We demonstrate the first cerebral blood flow map using MRI, and the first structural tractography from a live sea lion brain. COMPARISON WITH EXISTING METHODS: Scans were compared to prior anatomical and functional studies in live sea lions, and structural connectivity in post mortem specimens. Hippocampal volumes were broadly in line with prior studies, with differences likely attributable to the 3D approach used here. Functional connectivity of the dorsal left hippocampus matched that found in a prior study conducted at a lower magnetic field, while structural connectivity in the live brain agreed with findings observed in post mortem studies. CONCLUSIONS: Our protocol provides a comprehensive, longitudinal view of the functional and anatomical changes expected to result from DOM toxicosis. It can also screen for other common neurological pathologies and is suitable for any pinniped that can fit inside an MRI scanner.

Fast automatic segmentation of thalamic nuclei from MP2RAGE acquisition at 7 Tesla.

PURPOSE: Thalamic nuclei are largely invisible in conventional MRI due to poor contrast. Thalamus Optimized Multi-Atlas Segmentation (THOMAS) provides automatic segmentation of 12 thalamic nuclei using white-matter-nulled (WMn) Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence at 7T, but increases overall scan duration. Routinely acquired, bias-corrected Magnetization Prepared 2 Rapid Gradient Echo (MP2RAGE) sequence yields superior tissue contrast and quantitative T1 maps. Application of THOMAS to MP2RAGE has been investigated in this study. METHODS: Eight healthy volunteers and five pediatric-onset multiple sclerosis patients were recruited at Children's Hospital of Philadelphia and scanned at Siemens 7T with WMn-MPRAGE and multi-echo-MP2RAGE (ME-MP2RAGE) sequences. White-matter-nulled contrast was synthesized (MP2-SYN) from T1 maps from ME-MP2RAGE sequence. Thalamic nuclei were segmented using THOMAS joint label fusion algorithm from WMn-MPRAGE and MP2-SYN datasets. THOMAS pipeline was modified to use majority voting to segment bias corrected T1-weighted uniform (MP2-UNI) images. Thalamic nuclei from MP2-SYN and MP2-UNI images were evaluated against corresponding nuclei obtained from WMn-MPRAGE images using dice coefficients, volume similarity indices (VSIs) and distance between centroids. RESULTS: For MP2-SYN, dice > 0.85 and VSI > 0.95 was achieved for five larger nuclei and dice > 0.6 and VSI > 0.7 was achieved for seven smaller nuclei. The dice and VSI were slightly higher, whereas the distance between centroids were smaller for MP2-SYN compared to MP2-UNI, indicating improved performance using the MP2-SYN image. CONCLUSIONS: THOMAS algorithm can successfully segment thalamic nuclei in MP2RAGE images with essentially equivalent quality as WMn-MPRAGE, widening its applicability in studies focused on thalamic involvement in aging and disease.

Predicted disconnectome associated with progressive periventricular white matter ischemia.

We used a virtual lesion DTI fiber tracking approach with healthy subject DTI data and simulated periventricular white matter (PVWM) lesion masks to predict the sequence of connectivity changes associated with progressive PVWM ischemia. We found that the optic radiations, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, corpus callosum, temporopontine tract and fornix were affected in early simulated ischemic injury, and that the connectivity of subcortical, cerebellar, and visual regions were significantly disrupted with increasing simulated lesion severity. The results of this study provide insights into the spatial-temporal changes of the brain structural connectome under progressive PVWM ischemia. The virtual lesion approach provides a meaningful proxy to the spatial-temporal changes of the brain's structural connectome and can be used to further characterize the cognitive sequelae of progressive PVWM ischemia in both normal aging and dementia.

Reliability of arterial spin labeling derived cerebral blood flow in periventricular white matter.

We aimed to assess the reliability of cerebral blood flow (CBF) measured using arterial spin labeled (ASL) perfusion magnetic resonance imaging (MRI) from the periventricular white matter (PVWM) by computing its repeatability and comparing to [15O]-water Positron Emission Tomography (PET) as a reference. Simultaneous PET/MRI perfusion data were acquired twice in the same session, about 15 min apart, from 16 subjects (age: 41.4 ± 12.0 years, 9 female). ASL protocols used pseudocontinuous labeling (pCASL) with background-suppressed 3-dimensional readouts, and included both single and multiple post labeling delay (PLD) acquisitions, each acquired twice, with the latter providing both CBF and arterial transit time (ATT) maps. The reliability of ASL derived PVWM CBF was evaluated using intra-session repeatability assessed by the within-subject coefficient of variation (wsCV) of the PVWM CBF values obtained from the two scans, correlation with concurrently-acquired PET CBF values, and by comparing them with that measured in other commonly used regions of interest (ROIs) such as whole brain (WB), gray matter (GM) and white matter (WM). The wsCVs for PVWM CBF with single and multi-PLD acquisitions were 5.7 (95% CI: (3.4,7.7)) % and 6.1 (95% CI: (3.8,8.3))%, which were similar to those obtained from WB, GM and WM CBF even though the PVWM region is the most weakly perfused region of brain parenchyma. Correlations between relative PVWM CBF derived from ASL and from [15O]-water PET were also comparable to the other ROIs. Finally, the ATT of the PVWM region was found to be 1.27 ± 0.27s, which was not an outlier for the arterial circulation of the brain. These findings suggest that PVWM CBF can be reliably measured with the current state-of-the-art ASL methods.

Relationship of Cerebral Blood Flow to Cognitive Function and Recovery in Early Chronic Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of morbidity worldwide, for which biomarkers are needed to better understand the underlying pathophysiology. Microvascular injury represents a subset of pathological mechanisms contributing to cognitive dysfunction after TBI, which may also impair subsequent neural repair thereby inhibiting cognitive recovery. Magnetic resonance imaging (MRI)-based measurement of cerebral blood flow (CBF) by arterial spin labeling (ASL) provides an appealing means of assessing microvascular disruption in TBI; however, the relationship between CBF alterations in the early chronic post-TBI setting and cognitive dysfunction as well as subsequent cognitive recovery remain poorly understood. Structural MRI and ASL were performed in 42 TBI subjects 3 months post-injury and 35 matched healthy controls. Neuropsychological testing was performed in each subject, as well as in a subset of TBI patients (n = 33) at 6 and/or 12 months post-injury. TBI and control subject CBF data were compared between groups in a voxel-wise fashion while controlling for the effects of structural atrophy. A region-of-interest approach was then used to compare CBF to clinical and neuropsychological measures within the TBI group in a cross-sectional fashion, as well as to the degree of subsequent cognitive recovery among subjects with follow-up testing. At 3 months post-injury, the TBI group demonstrated lower performance in each cognitive domain (p < 0.05), as well as widespread reductions in gray matter CBF independent of structural atrophy (p < 0.05). Within the TBI group, CBF was moderately correlated with injury severity (r = -0.43; p = 0.009) and executive function (r = 0.43; p = 0.01). In the longitudinal analysis, there was a positive correlation between initial CBF and processing speed recovery (r = 0.43; p = 0.015) independent of age, education level, and initial test score. Early chronic TBI is associated with widespread gray matter CBF deficits, which are correlated with injury severity and cognitive dysfunction. CBF may predict subsequent recovery in some cognitive domains.