Mechanistic insights on age-related changes in heart-aorta-brain hemodynamic coupling using a pulse wave model of the entire circulatory system.

Age-related changes in aortic biomechanics can impact the brain by reducing blood flow and increasing pulsatile energy transmission. Clinical studies have shown that impaired cardiac function in patients with heart failure is associated with cognitive impairment. Although previous studies have attempted to elucidate the complex relationship between age-associated aortic stiffening and pulsatility transmission to the cerebral network, they have not adequately addressed the effect of interactions between aortic stiffness and left ventricle (LV) contractility (neither on energy transmission nor on brain perfusion). In this study, we use a well-established and validated one-dimensional blood flow and pulse wave computational model of the circulatory system to address how age-related changes in cardiac function and vasculature affect the underlying mechanisms involved in the LV-aorta-brain hemodynamic coupling. Our results reveal how LV contractility affects pulsatile energy transmission to the brain, even with preserved cardiac output. Our model demonstrates the existence of an optimal heart rate (near the normal human heart rate) that minimizes pulsatile energy transmission to the brain at different contractility levels. Our findings further suggest that the reduction in cerebral blood flow at low levels of LV contractility is more prominent in the setting of age-related aortic stiffening. Maintaining optimal blood flow to the brain requires either an increase in contractility or an increase in heart rate. The former consistently leads to higher pulsatile power transmission, and the latter can either increase or decrease subsequent pulsatile power transmission to the brain.NEW & NOTEWORTHY We investigated the impact of major aging mechanisms of the arterial system and cardiac function on brain hemodynamics. Our findings suggest that aging has a significant impact on heart-aorta-brain coupling through changes in both arterial stiffening and left ventricle (LV) contractility. Understanding the underlying physical mechanisms involved here can potentially be a key step for developing more effective therapeutic strategies that can mitigate the contributions of abnormal LV-arterial coupling toward neurodegenerative diseases and dementia.

White matter hyperintensities and their relationship to cognition: Effects of segmentation algorithm.

White matter hyperintensities (WMHs) are brain white matter lesions that are hyperintense on fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans. Larger WMH volumes have been associated with Alzheimer's disease (AD) and with cognitive decline. However, the relationship between WMH volumes and cross-sectional cognitive measures has been inconsistent. We hypothesize that this inconsistency may arise from 1) the presence of AD-specific neuropathology that may obscure any WMH effects on cognition, and 2) varying criteria for creating a WMH segmentation. Manual and automated programs are typically used to determine segmentation boundaries, but criteria for those boundaries can differ. It remains unclear whether WMH volumes are associated with cognitive deficits, and which segmentation criteria influence the relationships between WMH volumes and clinical outcomes. In a sample of 260 non-demented participants (ages 55-90, 141 males, 119 females) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we compared the performance of five WMH segmentation methods, by relating the WMH volumes derived using each method to both clinical diagnosis and composite measures of executive function and memory. To separate WMH effects on cognition from effects related to AD-specific processes, we performed analyses separately in people with and without abnormal cerebrospinal fluid amyloid levels. WMH volume estimates that excluded more diffuse, lower-intensity lesions were more strongly correlated with clinical diagnosis and cognitive performance, and only in those without abnormal amyloid levels. These findings may inform best practices for WMH segmentation, and suggest that AD neuropathology may mask WMH effects on clinical diagnosis and cognition.

No-reflow phenomenon in the heart and brain.

The no-reflow phenomenon refers to the observation that when an organ is made ischemic by occlusion of a large artery supplying it, restoration of patency in that artery does not restore perfusion to the microvasculature supplying the parenchyma of that organ. This has been observed after prolonged arterial occlusions in the heart (30-90 min), brain, skin, and kidney. In experimental models, zones of no reflow in the heart are characterized by ultrastructural microvascular damage, including focal endothelial swelling obstructing the lumen of small vessels. Blood elements such as neutrophil plugs, platelets, and stacking of erythrocytes have also been implicated. No reflow is associated with poor healing of the myocardial infarction. In patients, no reflow is associated with a poor clinical outcome independent of infarct size, suggesting that therapy for no reflow may be an important approach to improving outcome for ST elevation myocardial infarction. No reflow occurs after reperfusion of experimental cerebral ischemia and may be observed after only 5-min episodes of ischemia. Aggregation of blood elements may play a greater role than in cardiac no reflow. No reflow in the brain may involve cortical spreading depression with disturbed local vascular control and high, vasculotonic levels of extracellular K+ concentration, postischemic swelling in endothelial cells and abutting end feet of pericytes, pericyte contraction and death, interstitial edema with collapse of cerebral capillaries, and inflammatory reaction. New guidelines suggesting that reperfusion for stroke may be considered as late as 24 h after the onset of symptoms suggest that clinicians may be seeing more no reflow in the future.

Genetic, anatomic, and clinical determinants of human serum sterol and vitamin D levels.

An unknown fraction of the genome participates in the metabolism of sterols and vitamin D, two classes of lipids with diverse physiological and pathophysiological roles. Here, we used mass spectrometry to measure the abundance of >60 sterol and vitamin D derivatives in 3,230 serum samples from a well-phenotyped patient population. Twenty-nine of these lipids were detected in a majority of samples at levels that varied over thousands of fold in different individuals. Pairwise correlations between sterol and vitamin D levels revealed evidence for shared metabolic pathways, additional substrates for known enzymes, and transcriptional regulatory networks. Serum levels of multiple sterols and vitamin D metabolites varied significantly by sex, ethnicity, and age. A genome-wide association study identified 16 loci that were associated with levels of 19 sterols and 25-hydroxylated derivatives of vitamin D (P < 10(-7)). Resequencing, expression analysis, and biochemical experiments focused on one such locus (CYP39A1), revealed multiple loss-of-function alleles with additive effects on serum levels of the oxysterol, 24S-hydroxycholesterol, a substrate of the encoded enzyme. Body mass index, serum lipid levels, and hematocrit were strong phenotypic correlates of interindividual variation in multiple sterols and vitamin D metabolites. We conclude that correlating population-based analytical measurements with genotype and phenotype provides productive insight into human intermediary metabolism.

Cardiovascular Risk Factors Associated with Smaller Brain Volumes in Regions Identified as Early Predictors of Cognitive Decline.

PURPOSE: To determine in a large multiethnic cohort the cardiovascular and genetic risk factors associated with smaller volume in the hippocampus, precuneus, and posterior cingulate, and their association with preclinical deficits in cognitive performance in patients younger and older than 50 years. MATERIALS AND METHODS: The institutional review board approved the study and all participants provided written informed consent. Eligible for this study were 1629 participants (700 men and 929 women; mean age, 50.0 years ± 10.2 [standard deviation]) drawn from the population-based Dallas Heart Study who underwent laboratory and clinical analysis in an initial baseline visit and approximately 7 years later underwent brain magnetic resonance imaging with automated volumetry and cognitive assessment with the Montreal Cognitive Assessment (MoCA). Regression analysis showed associations between risk factors and segmental volumes, and associations between these volumes with cognitive performance in participants younger and older than 50 years. RESULTS: Lower hippocampal volume was associated with previous alcohol consumption (standardized estimate, -0.04; P = .039) and smoking (standardized estimate, -0.04; P = .048). Several risk factors correlated with lower total brain, posterior cingulate, and precuneus volumes. Higher total (standardized estimate, 0.06; P = .050), high-density lipoprotein (standardized estimate, 0.07; P = .003), and low-density lipoprotein (standardized estimate, 0.04; P = .037) cholesterol levels were associated with larger posterior cingulate volume, and higher triglyceride levels (standardized estimate, 0.06; P = .004) were associated with larger precuneus volume. Total MoCA score was associated with posterior cingulate volume (standardized estimate, 0.13; P = .001) in younger individuals and with hippocampal (standardized estimate, 0.06; P < .05) and precuneus (standardized estimate, 0.08; P < .023) volumes in older adults. CONCLUSION: Smaller volumes in specific brain regions considered to be early markers of dementia risk were associated with specific cardiovascular disease risk factors and cognitive deficits in a predominantly midlife multiethnic population-based sample. Additionally, the risk factors most associated with these brain volumes differed in participants younger and older than 50 years, as did the association between brain volume and MoCA score.

Correction and optimization of a T2-based approach to map blood oxygenation in small cerebral veins.

PURPOSE: Cerebral venous blood oxygenation (Yv ) is an important biomarker in brain physiology and function. The present study proposes a procedure to provide a quantitative map of the brain's intravascular Yv. THEORY AND METHODS: The method is based on a pulse sequence, T2 -Relaxation-Under-Phase-Contrast (TRU-PC) MRI, with postprocessing approaches to correct eddy-current effects. A complete scan protocol consists of four TRU-PC scans sensitized to large and small vessels with anterior-posterior and foot-head flow-encoding directions, and the data are analyzed conjunctively. Eddy-current correction was performed by fitting the tissue phase to a hyperplane, and then subtracting the eddy-current phase from the measured vessel phase. The reproducibility of the Yv-maps was examined in five participants. Sensitivity of the Yv map to a caffeine challenge was studied in another five participants. RESULTS: Removal of eddy-current induced artifact allowed for the correction of T2 measurements, as demonstrated in vivo and with simulation. A Yv-map depicting all vessels in the slice can be obtained with the proposed protocol. Test-retest variability of the Yv -map was 3.7 ± 1.2%. Yv reduction can be reliably detected (P < 0.001) following the caffeine ingestion. CONCLUSION: With the proposed TRU-PC protocol and eddy-current correction procedure, an accurate, vessel-specific Yv map of the human brain can be obtained.

Relationship between leukoaraiosis, carotid intima-media thickness and intima-media thickness variability: Preliminary results.

OBJECTIVE: To assess the relationship between the degree of leukoaraiosis (LA), carotid intima-media thickness (IMT) and intima-media thickness variability (IMTV). MATERIALS AND METHODS: Sixty-one consecutive patients, who underwent a brain MRI examination and a carotid artery ultrasound, were included in this retrospective study, which conformed with the Declaration of Helsinki. Written informed consent was waived. In each patient, right/left carotid arteries and brain hemispheres were assessed using automated software for IMT, IMTV and LA volume. RESULTS: The mean hemispheric LA volume was 2,224 mm3 (SD 2,702 mm3) and there was no statistically significant difference in LA volume between the right and left hemispheres (p value = 0.628). The mean IMT and IMTV values were 0.866 mm (SD 0.170) and 0.143 mm (SD 0.100), respectively, without significant differences between the right and left sides (p values 0.733 and 0.098, respectively). The correlation coefficient between IMTV and LA volume was 0.41 (p value = 0.0001), and 0.246 (p value = 0.074) between IMT and LA volume. CONCLUSIONS: IMTV significantly correlates with LA volume. Further studies are warranted to verify whether this parameter can be used clinically as a marker of cerebrovascular risk. KEY POINTS: • Intima-media thickness variability (IMTV) significantly correlates with leukoaraiosis volume. • IMTV could be used as a marker for cerebrovascular risk. • IMTV seems to be a better predictor of weighted mean difference than IMT.

Effect of normal aging versus hypertension, abnormal body mass index, and diabetes mellitus on white matter hyperintensity volume.

BACKGROUND AND PURPOSE: The natural history of white matter hyperintensity (WMH) progression resulting from normal aging versus comorbid vascular insults remains unclear. Therefore we investigated age-related differences in WMH volumes among a group with comorbid hypertension, abnormal body mass index, and diabetes mellitus to a normal aging group drawn from the same population lacking any of these comorbidities. METHODS: WMH volumes were acquired using 3T MRI for 2011 Dallas Heart Study participants. The slope of the WMH versus age regression was compared between normal and comorbidity groups<50 and ≥50 years of age where a change in slope was demonstrated. RESULTS: Aging was linearly associated with greater log WMH volume for both normal (P=0.02) and comorbidity (P<0.0001) groups. Beyond 50 years of age, more rapid increases in WMH volumes for age were seen in the group with comorbidities (P<0.0001) but not in the normal group (P=0.173). The between-group difference in slope of expected WMH for age was significantly greater in the comorbidity groups≥50 years of age (P=0.0008) but not <50 years of age (P=0.752). CONCLUSIONS: After 50 years of age, but not before, comorbid hypertension, obesity, and diabetes mellitus were associated with significantly larger WMH volumes for age compared with a normal aging group lacking these conditions. These results support the assertion that age-related differences in WMH volumes are significantly increased in the presence of comorbidities, but the effect is only detectable after 50 years of age.

Fully automated tool to identify the aorta and compute flow using phase-contrast MRI: validation and application in a large population based study.

PURPOSE: To assess if fully automated localization of the aorta can be achieved using phase contrast (PC) MR images. MATERIALS AND METHODS: PC cardiac-gated MR images were obtained as part of a large population-based study. A fully automated process using the Hough transform was developed to localize the ascending aorta (AAo) and descending aorta (DAo). The study was designed to validate this technique by determining: (i) its performance in localizing the AAo and DAo; (ii) its accuracy in generating AAo flow volume and DAo flow volume; and (iii) its robustness on studies with pathological abnormalities or imaging artifacts. RESULTS: The algorithm was applied successfully on 1884 participants. In the randomly selected 50-study validation set, linear regression shows an excellent correlation between the automated (A) and manual (M) methods for AAo flow (r = 0.99) and DAo flow (r = 0.99). Bland-Altman difference analysis demonstrates strong agreement with minimal bias for: AAo flow (mean difference [A-M] = 0.47 ± 2.53 mL), and DAo flow (mean difference [A-M] = 1.74 ± 2.47 mL). CONCLUSION: A robust fully automated tool to localize the aorta and provide flow volume measurements on phase contrast MRI was validated on a large population-based study.

Cardiovascular outcome associations among cardiovascular magnetic resonance measures of arterial stiffness: the Dallas heart study.

BACKGROUND: Cardiovascular magnetic resonance (CMR) has been validated for the noninvasive assessment of total arterial compliance and aortic stiffness, but their associations with cardiovascular outcomes is unknown. The purpose of this study was to evaluate associations of CMR measures of total arterial compliance and two CMR measures of aortic stiffness with respect to future cardiovascular events. METHODS: The study consisted of 2122 Dallas Heart Study participants without cardiovascular disease who underwent CMR at 1.5 Tesla. Aortic stiffness was measured by CMR-derived ascending aortic distensibility and aortic arch pulse wave velocity. Total arterial compliance was calculated by dividing left ventricular stroke volume by pulse pressure. Participants were monitored for cardiovascular death, non-fatal cardiac events, and non-fatal extra-cardiac vascular events over 7.8 ± 1.5 years. Cox proportional hazards regression was used to assess for associations between CMR measures and cardiovascular events. RESULTS: Age, systolic blood pressure, and resting heart rate were independently associated with changes in ascending aortic distensibility, arch pulse wave velocity, and total arterial compliance (all p < .0001). A total of 153 participants (6.9%) experienced a cardiovascular event. After adjusting for traditional risk factors, total arterial compliance was modestly associated with increased risk for composite events (HR 1.07 per 1SD, p = 0.03) while the association between ascending aortic distensibility and composite events trended towards significance (HR 1.18 per 1SD, p = 0.08). Total arterial compliance and aortic distensibility were independently associated with nonfatal cardiac events (HR 1.11 per 1SD, p = 0.001 and HR 1.45 per 1SD, p = 0.0005, respectively), but not with cardiovascular death or nonfatal extra-cardiac vascular events. Arch pulse wave velocity was independently associated with nonfatal extra-cardiac vascular events (HR 1.18 per 1SD, p = 0.04) but not with cardiovascular death or nonfatal cardiac events. CONCLUSIONS: In a multiethnic population free of cardiovascular disease, CMR measures of arterial stiffness are associated with future cardiovascular events. Total arterial compliance and aortic distensibility may be stronger predictors of nonfatal cardiac events, while pulse wave velocity may be a stronger predictor of nonfatal extra-cardiac vascular events.

Physiologic underpinnings of negative BOLD cerebrovascular reactivity in brain ventricles.

With a growing need for specific biomarkers in vascular diseases, there has been a surging interest in mapping cerebrovascular reactivity (CVR) of the brain. This index can be measured by conducting a hypercapnia challenge while acquiring blood-oxygenation-level-dependent (BOLD) signals. A BOLD signal increase with hypercapnia is the expected outcome and represents the majority of literature reports; in this work we report an intriguing observation of an apparently negative BOLD CVR response at 3T, during inhalation of 5% CO2 with balance medical air. These "negative-CVR" clusters were specifically located in the ventricular regions of the brain, where CSF is abundant and results in an intense baseline signal. The amplitude of the CVR response was -0.51±0.44% (N=14, age 26±4 years). We hypothesized that this observation might not be due to a decrease in oxygenation but rather a volume effect in which bright CSF signal is replaced by a less intensive blood signal as a result of vasodilation. To test this, we performed an inversion-recovery (IR) experiment to suppress the CSF signal (N=10, age 27±5 years). This maneuver in imaging sequence reversed the sign of the signal response (to 0.66±0.25%), suggesting that the volume change was the predominant reason for the apparently negative CVR in the BOLD experiment. Further support of this hypothesis was provided by a BOLD hyperoxia experiment, in which no voxels showed a negative response, presumably because vasodilation is not usually associated with this challenge. Absolute CBF response to hypercapnia was measured in a new group of subjects (N=8, age 29±7 years) and it was found that CBF in ventricular regions increased by 48% upon CO2 inhalation, suggesting that blood oxygenation most likely increased rather than decreased. The findings from this study suggest that CO2 inhalation results in the dilation of ventricular vessels accompanied by shrinkage in CSF space, which is responsible for the apparently negative CVR in brain ventricles.

White matter hyperintensities: use of aortic arch pulse wave velocity to predict volume independent of other cardiovascular risk factors.

PURPOSE: To evaluate the relationship between pulse wave velocity (PWV) from the aortic arch and subsequent cerebral microvascular disease independent of other baseline cardiovascular risk factors among the participants in the multiethnic Dallas Heart Study. MATERIALS AND METHODS: Each subject gave written consent to participate in this HIPAA-compliant, institutional review board-approved prospective study. Aortic arch PWV was measured with phase-contrast magnetic resonance (MR) imaging in a population sample (n = 1270) drawn from the probability-based Dallas Heart Study. Seven years later, the volume of white matter hyperintensities (WMHs) was determined from brain MR images. Linear regression was conducted with aortic arch PWV, 15 other cardiovascular risk factors, and age, sex, and ethnicity included as predictors of WMH. The authors implemented a smoothly clipped absolute deviation-penalized variable selection method to evaluate an optimal predictive risk factor model. RESULTS: Aortic arch PWV helped predict WMH volume independent of the other demographic and cardiovascular risk factors (regression coefficient: 0.29; standard error: 0.06; 95% confidence interval: 0.17, 0.42; P < .0001). The optimal predictor variables of subsequent WMH volume adjusted for sex and ethnicity included aortic arch PWV, age, systolic blood pressure, hypertension treatment, and congestive heart failure. The authors estimated that a 1% increase in aortic arch PWV (in meters per second) is related to a 0.3% increase in subsequent WMH volume (in milliliters) when all other variables in the model are held constant. CONCLUSION: Aortic arch PWV measured with phase-contrast MR imaging is a highly significant independent predictor of subsequent WMH volume, with a higher standardized effect than any other cardiovascular risk factor assessed except for age. In an optimal predictive model of subsequent WMH burden, aortic arch PWV provides a distinct contribution along with systolic blood pressure, hypertension treatment, congestive heart failure, and age.

Automated quantification of white matter disease extent at 3 T: comparison with volumetric readings.

PURPOSE: To develop and validate an algorithm to automatically quantify white matter hyperintensity (WMH) volume. MATERIALS AND METHODS: Images acquired as part of the Dallas Heart Study, a multiethnic, population-based study of cardiovascular health, were used to develop and validate the algorithm. 3D magnetization prepared rapid acquisition gradient echo (MP-RAGE) and 2D fluid-attenuated inversion recovery (FLAIR) images were acquired from 2082 participants. Images from 161 participants (7.7% of the cohort) were used to set an intensity threshold to maximize the agreement between the algorithm and a qualitative rating made by a radiologist. The resulting algorithm was run on the entire cohort and outlier analyses were used to refine the WMH volume measurement. The refined, automatic WMH burden estimate was then compared to manual quantitative measurements of WMH volume in 28 participants distributed across the range of volumes seen in the entire cohort. RESULTS: The algorithm showed good agreement with the volumetric readings of a trained analyst: the Spearman's Rank Order Correlation coefficient was r = 0.87. Linear regression analysis showed a good correlation WMHml[automated] = 1.02 × WMHml[manual] - 0.48. Bland-Altman analysis showed a bias of 0.34 mL and a standard deviation of 2.8 mL over a range of 0.13 to 41 mL. CONCLUSION: We have developed an algorithm that automatically estimates the volume of WMH burden using an MP-RAGE and a FLAIR image. This provides a tool for evaluating the WMH burden of large populations to investigate the relationship between WMH burden and other health factors.

Vascular risk profile and white matter hyperintensity volume among Mexican Americans and non-Hispanic Whites: The HABLE study.

INTRODUCTION: Among vascular risk factors we hypothesized that an increased prevalence of diabetes in Hispanics would be associated with greater white matter hyperintensity (WMH) volume, which may contribute to cognitive decline. METHODS: A total of 1318 participants (60% female; 49% Hispanic, 51% non-Hispanic White; age 66.2 ± 8.9 years) underwent clinical evaluation and brain magnetic resonance imaging (MRI). WMH volume associations were assessed with age, sex, and ethnicity and then with vascular risk factors in a selective regression model. RESULTS: WMH volume was greater with older age (P < .0001), Hispanic ethnicity (P = .02), and female sex (P = .049). WMH volume was best predicted by age, diastolic blood pressure, hypertension history, hemoglobin A1c (HbA1c), white blood cell count, and hematocrit (P < .01 for all). Elevated HbA1c was associated with greater WMH volume among Hispanics (parameter estimate 0.08 ± 0.02, P < .0001) but not non-Hispanic Whites (parameter estimate 0.02 ± 0.04, P = .5). DISCUSSION: WMH volume was greater in Hispanics, which may be partly explained by increased WMH volume related to elevated HbA1c among Hispanics but not non-Hispanic Whites.

Algorithms for segmenting cerebral time-of-flight magnetic resonance angiograms from volunteers and anemic patients.

Purpose: To evaluate six cerebral arterial segmentation algorithms in a set of patients with a wide range of hemodynamic characteristics to determine real-world performance. Approach: Time-of-flight magnetic resonance angiograms were acquired from 33 subjects: normal controls ( N = 11 ), sickle cell disease ( N = 11 ), and non-sickle anemia ( N = 11 ) using a 3 Tesla Philips Achieva scanner. Six segmentation algorithms were tested: (1) Otsu's method, (2) K-means, (3) region growing, (4) active contours, (5) minimum cost path, and (6) U-net machine learning. Segmentation algorithms were tested with two region-selection methods: global, which selects the entire volume; and local, which iteratively tracks the arteries. Five slices were manually segmented from each patient by two readers. Agreement between manual and automatic segmentation was measured using Matthew's correlation coefficient (MCC). Results: Median algorithm segmentation times ranged from 0.1 to 172.9 s for a single angiogram versus 10 h for manual segmentation. Algorithms had inferior performance to inter-observer vessel-based ( p < 0.0001 , MCC = 0.65 ) and voxel-based ( p < 0.0001 , MCC = 0.73 ) measurements. There were significant differences between algorithms ( p < 0.0001 ) and between patients ( p < 0.0042 ). Post-hoc analyses indicated (1) local minimum cost path performed best with vessel-based ( p = 0.0261 , MCC = 0.50 ) and voxel-based ( p = 0.0131 , MCC = 0.66 ) analyses; and (2) higher vessel-based performance in non-sickle anemia ( p = 0.0002 ) and lower voxel-based performance in sickle cell ( p = 0.0422 ) compared with normal controls. All reported MCCs are medians. Conclusions: The best-performing algorithm (local minimum cost path, voxel-based) had 9.59% worse performance than inter-observer agreement but was 3 orders of magnitude faster. Automatic segmentation was non-inferior in patients with sickle cell disease and superior in non-sickle anemia.

Regional relationships between CSF VEGF levels and Alzheimer's disease brain biomarkers and cognition.

Vascular endothelial growth factor (VEGF) is a complex signaling protein that supports vascular and neuronal function. Alzheimer's disease (AD) -neuropathological hallmarks interfere with VEGF signaling and modify previously detected positive associations between cerebral spinal fluid (CSF) VEGF and cognition and hippocampal volume. However, it remains unknown 1) whether regional relationships between VEGF and glucose metabolism and cortical thinning exist, and 2) whether AD-neuropathological hallmarks (CSF Aß, t-tau, p-tau) also modify these relationships. We addressed this in 310 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (92 cognitively normal, 149 mild cognitive impairment, 69 AD; 215 CSF Aß+, 95 CSF Aß-) with regional cortical thickness and cognition measurements and 158 participants with FDG-PET. In Aß + participants (CSF Aß42 ≤ 192 pg/mL), higher CSF VEGF levels were associated with greater FDG-PET signal in the inferior parietal, and middle and inferior temporal cortices. Abnormal CSF amyloid and tau levels strengthened the positive association between VEGF and regional FDG-PET indices. VEGF also had both direct associations with semantic memory, as well as indirect associations mediated by regional FDG-PET signal to cognition.

MRI Automated T1 Signal Intensity Detection of Diffuse Brain Manganese Accumulation in Cirrhosis.

BACKGROUND AND PURPOSE: Cirrhosis is associated with diffuse brain manganese deposition, which results in increased signal intensity (SI) in the brain on T1-weighted images, most often visualized in the globus pallidus. The purpose of this study was to determine if automated image intensity measurements can detect SI differences in the basal ganglia and other regions reported to have manganese deposition in patients with cirrhosis compared with controls. METHODS: T1 FSPGR images were acquired on 28 patients with cirrhosis and 28 age-sex-matched controls. FreeSurfer T1 SI values were obtained for the globus pallidus, putamen, cerebral white matter, cerebral cortex, and brainstem. SI ratios were computed for globus pallidus normalized to white matter and brainstem. SI values and SI ratios were compared between groups using t-tests. RESULTS: Among people with cirrhosis, T1 SI was significantly increased in the globus pallidus, putamen, cerebral white matter, cerebral cortex, and brainstem (P< .001), and the globus pallidus to brainstem ratio was significantly increased (P< .001). No significant difference was seen for globus pallidus to cerebral white matter T1 SI ratio (P = .38). CONCLUSIONS: Automatic assessment of T1 SI allows for rapid, objective identification of widespread T1 shortening associated with manganese deposition in cirrhosis, consistent with the global deposition of neurotoxic manganese seen in pathology studies. This automated T1 assessment may have broader utility for other conditions beyond cirrhosis impacting T1 SI.

Dynamic Effects of Aortic Arch Stiffening on Pulsatile Energy Transmission to Cerebral Vasculature as A Determinant of Brain-Heart Coupling.

Aortic stiffness increases with age and is a robust predictor of brain pathology including Alzheimer's and other dementias. Aging causes disproportionate stiffening of the aorta compared with the carotid arteries, reducing protective impedance mismatches at their interface and affecting transmission of destructive pulsatile energy to the cerebral circulation. Recent clinical studies have measured regional stiffness within the aortic arch using pulse wave velocity (PWV) and have found a stronger association with cerebrovascular events than global stiffness measures. However, effects of aortic arch PWV on the transmission of harmful excessive pulsatile energy to the brain is not well-understood. In this study, we use an energy-based analysis of hemodynamic waves to quantify the effect of aortic arch stiffening on transmitted pulsatility to cerebral vasculature, employing a computational approach using a one-dimensional model of the human vascular network. Results show there exists an optimum wave condition-occurring near normal human heart rates-that minimizes pulsatile energy transmission to the brain. This indicates the important role of aortic arch biomechanics on heart-brain coupling. Our results also suggest that energy-based indices of pulsatility combining pressure and flow data are more sensitive to increased stiffness than using flow or pressure pulsatility indices in isolation.

Brain MR Spectroscopy Markers of Encephalopathy Due to Nonalcoholic Steatohepatitis.

BACKGROUND AND PURPOSE: In hepatic encephalopathy (HE), osmotic stressors promoting brain edema result in a compensatory drop in the astrocyte metabolite myo-inositol (mI). Identifying differences between nonalcoholic steatohepatitis (NASH) with and without HE and healthy controls using proton magnetic resonance spectroscopy (MRS) and evaluating hypoalbuminemia and hyperammonemia as osmotic stressors that predict the reduction of mI allow further understanding of mechanisms that promote brain edema in HE. The aim of this study was to assess brain edema in HE using characteristic MRS markers and serum albumin. METHODS: We evaluated between group differences among 19 NASH cirrhosis without HE (Crhs-HE) (age = 63 ± 8.7), 9 NASH cirrhosis with HE (Crhs+HE) (age = 63 ± 9.2), and 16 controls (age = 57.8 ± 11.7) using 1 H MRS. Glutamine (Gln/tCr) and serum albumin were evaluated as predictors of myo-inositol (mI/tCr) using linear regression. Statistical significance was set at P < .05 with adjustment for multiple comparisons. RESULTS: Brain mI/tCr was decreased, and Gln/tCr increased in Crhs+HE compared to Crhs-HE and controls in both brain regions (P < .001 for all). Evaluated together as joint predictors, serum albumin but not Gln/tCr significantly predicted mI/tCr in GM (P = .02 and P = .2, respectively) and PWM (P = .01 and P = .1, respectively). CONCLUSION: Low mI/tCr and increased Gln/tCr were characteristics of Crhs+HE. Low serum albumin was the strongest predictor of brain osmotic stress indicated by reduced mI/tCr, with no residual independent association seen for brain Gln/tCr concentration. This suggests that hypoalbuminemia in chronic liver disease may promote brain edema in HE.

Group delay method for MRI aortic pulse wave velocity measurements in clinical protocols with low temporal resolution: Validation in a heterogeneous cohort.

BACKGROUND: MRI assessment of aortic pulse wave velocity (PWV) helps predict the risk of vascular events, but the recommended phase contrast sampling rate is faster than what is utilized in most clinical sequences. There are many existing MRI databases obtained for assessment of cardiac output using lower temporal frequency sampling where information might be obtained about aortic stiffness (PWV). In this work, we sought to evaluate whether the Group Delay (GD) method can generate a reproducible measure of stiffness and describe expected age-related stiffening of the aortic arch using lower sampling rates in standard clinical sequences. METHODS: Phase contrast (PC) MRI was obtained on the ascending and descending aortic arch in a heterogeneous adult cohort (n = 23; 9 women) spanning over a wide range of ages (ages 24-89, mean 49.4 ± 18.4). Data was collected with standard cardiac MRI protocols for cardiac output evaluation (repetition time = 7.8 ms, views-per-segment = 4, encoding velocity = 200 cm/s). Pulse wave transit times (TT) were computed using the GD method, two other validated automated approaches (cross correlation TT Algorithm by Gaddum and Segment by Medviso), and the manual tangent method. Pressure waveforms from tonometry and flow waveforms from PC MRI were used to assess wave reflections. RESULTS: Group Delay and TT-Algorithm showed significant and high retest reproducibility (r = 0.86 for both) as well as high PWV correlation with age (r = 0.93, P-value < 0.00005 and r = 0.96, P-value < 0.00005 respectively) and with each other (r = 0.94, P-value < 0.00001, RMSE = 0.94 m/s). Arbitrary altering of the image acquisition trigger in the GD method introduced error of 10%-13%, but the TT-algorithm error range was 11%-25%. CONCLUSION: Group Delay enables reproducible assessment of transit time to derive PWV from low temporal resolution clinical cardiac MRI sequences that can also identify age-related stiffening.