ASL
Argininosuccinate lyase (EC 4.3.2.1) (ASAL) (Arginosuccinase)
Publications[править]
A fundamental goal in the drive to understand and find better treatments for dementia is the identification of the factors that render the aging brain vulnerable to neurodegenerative disease. Recent evidence indicates the integrity of the blood-brain barrier (BBB) to be an important component of functional failure underlying age-related cognitive decline. Practical and sensitive measurement is necessary, therefore, to support diagnostic and therapeutic strategies targeted at maintaining BBB integrity in aging patients. Here, we investigated changes in BBB permeability to endogenous blood water in the aging brain. A multiple-echo-time arterial spin-labeling MRI technique, implemented on a 9.4T Bruker imaging system, was applied to 7- and 27-month-old mice to measure changes in water permeability across the BBB with aging. We observed that BBB water permeability was 32% faster in aged mice. This occurred along with a 2.1-fold increase in mRNA expression of aquaporin-4 water channels and a 7.1-fold decrease in mRNA expression of α-syntrophin protein, which anchors aquaporin-4 to the BBB. Age-related changes to water permeability across the BBB can be captured using noninvasive noncontrast MRI techniques.
Keywords
- aging
- aquaporin-4
- arterial spin labeling
- blood-brain barrier
- blood-brain interface
- water permeability
Cerebrovascular reactivity (CVR) is an index of the dilatory function of cerebral blood vessels and has shown great promise in the diagnosis of risk factors in cerebrovascular disease. Aging is one such risk factor; thus, it is important to characterize age-related differences in CVR. CVR can be measured by BOLD MRI but few studies have measured quantitative cerebral blood flow (CBF)-based CVR in the context of aging. This study aims to determine the age effect on CVR using two quantitative CBF techniques, phase-contrast (PC), and arterial spin labeling (ASL) MRI. In 49 participants (32 younger and 17 older), CVR was measured with PC, ASL, and BOLD MRI. These CVR methods were compared across young and older groups to determine their dependence on age. PC and ASL CVR were also studied for inter-correlation and mean differences. Gray and white matter CVR values were also studied. PC CVR was higher in younger participants than older participants (by 17%, [i]p[/i] = 0.046). However, there were no age differences in ASL or BOLD CVR. ASL CVR was significantly correlated with PC CVR ([i]p[/i] = 0.042) and BOLD CVR ([i]p[/i] = 0.016), but its values were underestimated compared to PC CVR ([i]p[/i] = 0.045). ASL CVR map revealed no difference between gray matter and white matter tissue types, whereas gray matter was significantly higher than white matter in the BOLD CVR map. This study compared two quantitative CVR techniques in the context of brain aging and revealed that PC CVR is a more sensitive method for detection of age differences, despite the absence of spatial information. The ASL method showed a significant correlation with PC and BOLD, but it tends to underestimate CVR due to confounding factors associated with this technique. Importantly, our data suggest that there is not a difference in CBF-based CVR between the gray and white matter, in contrast to previous observation using BOLD MRI.
Keywords
- MRI
- aging
- arterial spin labeling
- cerebrovascular reactivity
- phase-contrast
Blood Oxygen Level Dependent (BOLD) functional MRI is a complex neurovascular signal whose magnitude depends on baseline physiological factors such as cerebral blood flow (CBF). Because baseline CBF varies across the brain and is altered with aging, the interpretation of stand-alone aging-related BOLD changes can be misleading. The primary objective of this study was to develop a methodology that combines task fMRI and arterial spin labeling (ASL) techniques to sensitize task-induced BOLD activity by covarying out the baseline physiology (i.e., CBF) in an aging model. We recruited 11 younger and 13 older healthy participants who underwent ASL and an overt language fMRI task (semantic category member generation). We measured in-scanner language performance to investigate the effect of BOLD sensitization on BOLD-behavior relationships. The results demonstrate that our correction approach is effective at enhancing the specificity and sensitivity of the BOLD signal in both groups. In addition, the correction strengthens the statistical association between task BOLD activity and behavioral performance. Although CBF has inherent age dependence, our results show that retaining the age factor within CBF aides in greater sensitization of task fMRI signals. From a cognitive standpoint, compared to young adults, the older participants showed a delayed domain-general language-related task activity possibly due to compromised vessel compliance. Further, assessment of functional evolution of corrected BOLD activity revealed biphasic BOLD dynamics in both groups where BOLD deactivation may reflect greater semantic demand or increased premium on domain general executive functioning in response to task difficulty. Although it was promising to note that the predictability of behavior using the proposed methodology outperforms other methodologies (i.e., no correction and normalization by division), and provides moderate stability and adequate power, further work with a larger cohort and other task designs is necessary to improve the stability of predicting associated behavior. In summary, we recommend correction of task fMRI signals by covarying out baseline CBF especially when comparing groups with different neurovascular properties. Given that ASL and BOLD fMRI are well established and widely employed techniques, our proposed multi-modal methodology can be readily implemented into data processing pipelines to obtain more accurate BOLD activation maps.
Keywords
- BOLD deactivation
- aging
- cerebral blood flow
- domain-general
- language fMRI
- semantic fluency
- sensitization
Adequate cerebral blood flow (CBF) is necessary to maintain brain metabolism and function. Arterial spin labeling (ASL) is an emerging MRI technique offering a non-invasive and reliable quantification of CBF. The genetic basis of CBF has not been well documented, and one approach to investigate this is to examine its heritability. The current study aimed to examine the heritability of CBF using ASL data from a cohort of community-dwelling older twins (41 monozygotic (MZ) and 25 dizygotic (DZ) twin pairs; age range, 65-93 years; 56.4% female). The results showed that the cortex had higher CBF than subcortical gray matter (GM) regions, and CBF in the GM regions of the anterior cerebral artery (ACA) territory was lower than that of the middle (MCA) and posterior (PCA) cerebral arteries. After accounting for the effects of age, sex and scanner, moderate heritability was identified for global CBF ([i]h[/i] = 0.611; 95% CI = 0.380-0.761), as well as for cortical and subcortical GM and the GM in the major arterial territories ([i]h[/i] = 0.500-0.612). Strong genetic correlations (GCs) were found between CBF in subcortical and cortical GM regions, as well as among the three arterial territories (ACA, MCA, PCA), suggesting a largely convergent genetic control for the CBF in brain GM. The moderate heritability of CBF warrants future investigations to uncover the genetic variants and genes that regulate CBF.
Keywords
- aging
- cerebral blood flow
- community-dwelling
- heritability
- twin study
Cerebral perfusion declines across the lifespan and is altered in the early stages of several age-related neuropathologies. Little is known, however, about the longitudinal evolution of perfusion in healthy older adults, particularly when perfusion is quantified using magnetic resonance imaging with arterial spin labeling (ASL). The objective was to characterize longitudinal perfusion in typically aging adults and elucidate associations with cognition and brain structure. Adults who were functionally intact at baseline (n = 161, ages 47-89) underwent ASL imaging to quantify whole-brain gray matter perfusion; a subset (n = 136) had repeated imaging (average follow-up: 2.3 years). Neuropsychological testing at each visit was summarized into executive function, memory, and processing speed composites. Global gray matter volume, white matter microstructure (mean diffusivity), and white matter hyperintensities were also quantified. We assessed baseline associations among perfusion, cognition, and brain structure using linear regression, and longitudinal relationships using linear mixed effects models. Greater baseline perfusion, particularly in the left dorsolateral prefrontal cortex and right thalamus, was associated with better executive functions. Greater whole-brain perfusion loss was associated with worsening brain structure and declining processing speed. This study helps validate noninvasive MRI-based perfusion imaging and underscores the importance of cerebral blood flow in cognitive aging.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Brain
- Cognition
- Cross-Sectional Studies
- Diffusion Tensor Imaging
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Perfusion Imaging
Keywords
- arterial spin labeling
- cerebral blood flow
- diffusion tensor imaging
- executive functions
- neuroimaging
- older adults; thalamus; dorsolateral prefrontal cortex
- processing speed
Cerebral blood flow (CBF) estimates from arterial spin labelling (ASL) show unexplained variability in older populations. We studied the impact of variation of haematocrit (Hct) on CBF estimates in a tri-ethnic elderly population. Approval for the study was obtained from the Fulham Research Ethics Committee and participants gave written informed consent. Pseudo-continuous arterial spin labelling was performed on 493 subjects (age 55-90) from a tri-ethnic community-based cohort recruited in London. CBF was estimated using a simplified Buxton equation, with and without correction for Hct measured from blood samples. Differences in perfusion were compared, stratified by sex, ethnicity and diabetes. Results of Student's t tests were reported with effect size. Hct adjustment decreased CBF estimates in all categories except white European men. The decrease for women was 2.7 (3.0, 2.4) mL/100 g/min) (mean (95% confidence interval (CI)), p < 0.001 d = 0.38. The effect size differed by ethnicity with estimated mean perfusion in South Asian and African Caribbean women found to be lower by 3.0 (3.6, 2.5) mL/100 g/min, p < 0.001 d = 0.56 and 3.1 (3.6, 2.5) mL/100 g/min), p < 0.001 d = 0.48, respectively. Estimates of perfusion in subjects with diabetes decreased by 1.8 (2.3, 1.4) mL/100 g/min, p < 0.001 d = 0.23) following Hct correction. Correction for individual Hct altered sample frequency distributions of CBF values, especially in women of non-European ethnicity. ASL-derived CBF values in women, non-European ethnicities and individuals with diabetes are overestimated if calculations are not appropriately adjusted for individual Hct. • CBF quantification from ASL using a fixed Hct of 43.5%, as recommended in the ISMRM white paper, may lead to erroneous CBF estimations particularly in non-European and female subjects. • Individually measured Hct values improve the accuracy of CBF estimation and, if these are not available, an adjusted value according to gender, ethnicity or diabetes status should be considered. • Hct-corrected ASL could be potentially important for CBF threshold decision making in the fields of neurodegenerative disease and neuro-oncology.
MeSH Terms
- African Continental Ancestry Group
- Aged
- Aged, 80 and over
- Aging
- Asian Continental Ancestry Group
- Cerebrovascular Circulation
- Diabetes Mellitus, Type 2
- Female
- Hematocrit
- Humans
- Magnetic Resonance Angiography
- Male
- Middle Aged
- Neurodegenerative Diseases
- Reproducibility of Results
- Sex Characteristics
Keywords
- Ageing
- Cerebrovascular circulation
- Ethnic groups
- Haematocrit
The primary goal of this study was to evaluate arterial transit time (ATT) in exercise-stimulated calf muscles as a promising indicator of muscle function. Following plantar flexion, ATT was measured by dynamic contrast-enhanced (DCE) MRI in young and elderly healthy subjects and patients with peripheral artery disease (PAD). In the young healthy subjects, gastrocnemius ATT decreased significantly (P < 0.01) from 4.3 ± 1.5 to 2.4 ± 0.4 sec when exercise load increased from 4 lbs to 16 lbs. For the same load of 4 lbs, gastrocnemius ATT was lower in the elderly healthy subjects (3.2 ± 1.1 sec; P = 0.08) and in the PAD patients (2.4 ± 1.2 sec; P = 0.02) than in the young healthy subjects. While the sensitivity of the exercise-stimulated ATT is diagnostically useful, it poses a challenge for arterial spin labeling (ASL), a noncontrast MRI method for measuring muscle perfusion. As a secondary goal of this study, we assessed the impact of ATT on ASL-measured perfusion with ASL data of multiple post labeling delays (PLDs) acquired from a healthy subject. Perfusion varied substantially with PLD in the activated gastrocnemius, which can be attributed to the ATT variability as verified by a simulation. In conclusion, muscle ATT is sensitive to exercise intensity, and it potentially reflects the functional impact of aging and PAD on calf muscles. For precise measurement of exercise-stimulated muscle perfusion, it is recommended that ATT be considered when quantifying muscle ASL data.
MeSH Terms
- Adult
- Aged
- Aging
- Ankle
- Arteries
- Blood Flow Velocity
- Exercise
- Female
- Humans
- Magnetic Resonance Angiography
- Male
- Middle Aged
- Muscle, Skeletal
- Peripheral Arterial Disease
- Regional Blood Flow
Keywords
- Arterial spin labeling
- arterial transit time
- calf muscle
- perfusion
Coffee, wine and chocolate are three frequently consumed substances with a significant impact on cognition. In order to define the structural and cerebral blood flow correlates of self-reported consumption of coffee, wine and chocolate in old age, we assessed cognition and brain MRI measures in 145 community-based elderly individuals with preserved cognition (69 to 86 years). Based on two neuropsychological assessments during a 3-year follow-up, individuals were classified into stable-stable (52 sCON), intermediate (61 iCON) and deteriorating-deteriorating (32 dCON). MR imaging included voxel-based morphometry (VBM), tract-based spatial statistics (TBSS) and arterial spin labelling (ASL). Concerning behavior, moderate consumption of caffeine was related to better cognitive outcome. In contrast, increased consumption of wine was related to an unfavorable cognitive evolution. Concerning MRI, we observed a negative correlation of wine and VBM in bilateral deep white matter (WM) regions across all individuals, indicating less WM lesions. Only in sCON individuals, we observed a similar yet weaker association with caffeine. Moreover, again only in sCON individuals, we observed a significant positive correlation between ASL and wine in overlapping left parietal WM indicating better baseline brain perfusion. In conclusion, the present observations demonstrate an inverse association of wine and coffee consumption with cognitive performances. Moreover, low consumption of wine but also moderate to heavy coffee drinking was associated with better WM preservation and cerebral blood-flow notably in cognitively stable elders.
MeSH Terms
- Aged
- Aged, 80 and over
- Brain
- Caffeine
- Cerebrovascular Circulation
- Chocolate
- Coffee
- Cognition
- Cognitive Dysfunction
- Eating
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Neuropsychological Tests
- White Matter
- Wine
Keywords
- aging
- caffeine
- chocolate
- cognition
- wine
Olfactory impairment is present in up to 90% of patients with Alzheimer's disease (AD) and is present in certain cases of mild cognitive impairment (MCI), a transient phase between normal aging and dementia. Subjects affected by MCI have a higher risk of developing dementia compared to the general population, and studies have found that olfactory deficits could be an indicator of whether such a conversion might happen. Following these assumptions, aim of this study was to investigate olfactory perception in MCI patients. We recruited 12 MCI subjects (mean age 70 ± 6.7 years) through the Alzheimer Assessment Unit (UVA Unite) of ASL Lecce (Italy), and 12 healthy geriatric volunteers (HS) as the control group (mean age 64 ± 6.0 years), all of whom were first evaluated via a panel of neuropsychological tests. Subjects were asked to perform an olfactory recognition task involving two scents: rose and eucalyptus, administrated in the context of an oddball task during EEG recordings. Olfactory event-related potential (OERP) components N1 and Late Positive Potential (LPC) were then analyzed as measures of the sensorial and perceptive aspects of the olfactory response, respectively. It was determined that, in the MCI group, both the N1 and LPC components were significantly different compared to those of the HS group during the execution of the oddball task. In particular, the N1 amplitude, was reduced, while the LPC amplitude was increased, indicating that a degree of perceptive compensation can occur when sensorial function is impaired. Further, a correlation analysis, involving OERP components and neuropsychological battery scores, indicated that impairment of olfactory perception may share common pathways with impairments of the spatial system and long-term memory processing.
Keywords
- CSERP
- MCI
- OERP
- aging
- neurodegenerative processes
- olfactory perception
Type 2 diabetes mellitus (T2DM) increases risk for dementia, including Alzheimer's disease (AD). Many previous studies of brain changes underlying cognitive impairment in T2DM have applied conventional structural magnetic resonance imaging (MRI) to detect macrostructural changes associated with cerebrovascular disease such as white matter hyperintensities or infarcts. However, such pathology likely reflects end-stage manifestations of chronic decrements in cerebral blood flow (CBF). MRI techniques that measure CBF may (1) elucidate mechanisms that precede irreversible parenchymal damage and (2) serve as a marker of risk for cognitive decline. CBF measured with arterial spin labeling (ASL) MRI may be a useful marker of perfusion deficits in T2DM and related conditions. We examined associations among T2DM, CBF, and cognition in a sample of 49 well-characterized nondemented older adults. Along with a standard T1-weighted scan, a pseudocontinuous ASL sequence optimized for older adults (by increasing post-labeling delays to allow more time for the blood to reach brain tissue) was obtained on a 3T GE scanner to measure regional CBF in FreeSurfer derived regions of interest. Participants also completed a neuropsychological assessment. Results showed no significant differences between individuals with and without T2DM in terms of cortical thickness or regional brain volume. However, adjusting for age, sex, comorbid vascular risk factors, and reference CBF (postcentral gyrus) older adults with T2DM demonstrated reduced CBF in the hippocampus, and inferior temporal, inferior parietal, and frontal cortices. Lower CBF was associated with poorer memory and executive function/processing speed. When adjusting for diabetes, the significant associations between lower regional CBF and poorer executive function/processing speed remained. Results demonstrate that CBF is reduced in older adults with T2DM, and suggest that CBF alterations likely precede volumetric changes. Notably, relative to nondiabetic control participants, those with T2DM showed lower CBF in predilection sites for AD pathology (medial temporal lobe and inferior parietal regions). Findings augment recent research suggesting that perfusion deficits may underlie cognitive decrements frequently observed among older adults with T2DM. Results also suggest that CBF measured with ASL MRI may reflect an early and important marker of risk of cognitive impairment in T2DM and related conditions.
Keywords
- Alzheimer’s disease
- aging
- arterial spin labeling
- cerebral blood flow
- diabetes
- memory
- neuropsychology
- vascular risk
To analyze age-related cerebral blood flow (CBF) using arterial spin labeling (ASL) MRI in healthy subjects with multivariate principal component analysis (PCA). 50 healthy subjects (mean age 45.8 ± 18.5 years, range 21-85) had 3D structural MRI and pseudo-continuous ASL MRI at resting state. The relationship between CBF and age was examined with voxel-based univariate analysis using multiple regression and two-sample [i]t[/i]-test (median age 41.8 years as a cut-off). An age-related CBF pattern was identified using multivariate PCA. Age correlated negatively with CBF especially anteriorly and in the cerebellum. After adjusting by global value, CBF was relatively decreased with aging in certain regions and relatively increased in others. The age-related CBF pattern showed relative reductions in frontal and parietal areas and cerebellum, and covarying increases in temporal and occipital areas. Subject scores of this pattern correlated negatively with age ([i]R[/i] = 0.588; [i]P[/i] < 0.001) and discriminated between the older and younger subgroups ([i]P[/i] < 0.001). A distinct age-related CBF pattern can be identified with multivariate PCA using ASL MRI.
Keywords
- aging
- arterial spin labeling
- cerebral blood flow
- principal component analysis
- scaled subprofile model
Previous studies suggest that low emotional resilience may correspond with increased or over-active amygdala function. Complementary studies suggest that emotional resilience increases with age; older adults tend to have decreased attentional bias to negative stimuli compared to younger adults. Amygdala nuclei and related brain circuits have been linked to negative affect, and depressed patients have been demonstrated to have abnormal amygdala function. In the current study, we correlated psychological resilience measures with amygdala function measured with resting-state arterial spin-labelled (ASL) and blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in older adults with and without depression. Specifically, we targeted the basolateral, centromedial, and superficial nuclei groups of the amygdala, which have different functions and brain connections. High levels of psychological resilience correlated with lower basal levels of amygdala activity measured with ASL fMRI. High resilience also correlated with decreased connectivity between amygdala nuclei and the ventral default-mode network independent of depression status. Instead, lower depression symptoms were associated with higher connectivity between the amygdalae and dorsal frontal networks. Future multi-site studies with larger sample size and improved neuroimaging technologies are needed. Longitudinal studies that target resilience to naturalistic stressors will also be a powerful contribution to the field. Our results suggest that resilience in older adults is more closely related to function in ventral amygdala networks, while late-life depression is related to reduced connectivity between the amygdala and dorsal frontal regions.
MeSH Terms
- Aged
- Amygdala
- Brain Mapping
- Depressive Disorder
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Neural Pathways
- Resilience, Psychological
Keywords
- Aging
- Amygdala
- Late-life depression
- Resilience
- fMRI
Previous studies have indicated that aerobic exercise could reduce age related decline in cognition and brain functioning. Here we investigated the effects of aerobic exercise on intrinsic brain activity. Sixty sedentary healthy males and females (64-78 years) were randomized into either an aerobic exercise group or an active control group. Both groups recieved supervised training, 3 days a week for 6 months. Multimodal brain imaging data was acquired before and after the intervention, including 10 min of resting state brain functional magnetic resonance imaging (rs-fMRI) and arterial spin labeling (ASL). Additionally, a comprehensive battery of cognitive tasks assessing, e.g., executive function and episodic memory was administered. Both the aerobic and the control group improved in aerobic capacity (VO -peak) over 6 months, but a significant group by time interaction confirmed that the aerobic group improved more. Contrary to our hypothesis, we did not observe any significant group by time interactions with regard to any measure of intrinsic activity. To further probe putative relationships between fitness and brain activity, we performed [i]post hoc[/i] analyses disregarding group belongings. At baseline, VO -peak was negativly related to BOLD-signal fluctuations (BOLD ) in mid temporal areas. Over 6 months, improvements in aerobic capacity were associated with decreased connectivity between left hippocampus and contralateral precentral gyrus, and positively to connectivity between right mid-temporal areas and frontal and parietal regions. Independent component analysis identified a VO -related increase in coupling between the default mode network and left orbitofrontal cortex, as well as a decreased connectivity between the sensorimotor network and thalamus. Extensive exploratory data analyses of global efficiency, connectome wide multivariate pattern analysis (connectome-MVPA), as well as ASL, did not reveal any relationships between aerobic fitness and intrinsic brain activity. Moreover, fitness-predicted changes in functional connectivity did not relate to changes in cognition, which is likely due to absent cross-sectional or longitudinal relationships between VO -peak and cognition. We conclude that the aerobic exercise intervention had limited influence on patterns of intrinsic brain activity, although [i]post hoc[/i] analyses indicated that individual changes in aerobic capacity preferentially influenced mid-temporal brain areas.
Keywords
- ASL
- aerobic exercise
- aging
- brain plasticity
- fMRI
- resting-state
Regional cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) in young and elderly participants were assessed using pulsed arterial spin labeling (ASL) and blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) techniques in combination with inhalation of CO2. Pulsed ASL and BOLD-MRI were acquired in seventeen asymptomatic volunteers (10 young adults, age: 30±7 years; 7 elderly adults, age: 64±8 years) with no history of diabetes, hypertension, and neurological diseases. Data from one elderly participant was excluded due to the incorrigible head motion. Average baseline CBF in gray matter was significantly reduced in elderly (46±9 mL·100 g-1·min-1) compared to young adults (57±8 mL·100 g-1·min-1; P=0.02). Decreased pulsed ASL-CVR and BOLD-CVR in gray matter were also observed in elderly (2.12±1.30 and 0.13±0.06 %/mmHg, respectively) compared to young adults (3.28±1.43 and 0.28±0.11 %/mmHg, respectively; P<0.05), suggesting some degree of vascular impairment with aging. Moreover, age-related decrease in baseline CBF was observed in different brain regions (inferior, middle and superior frontal gyri; precentral and postcentral gyri; superior temporal gyrus; cingulate gyri; insula, putamen, caudate, and supramarginal gyrus). In conclusion, CBF and CVR were successfully investigated using a protocol that causes minimal or no discomfort for the participants. Age-related decreases in baseline CBF and CVR were observed in the cerebral cortex, which may be related to the vulnerability for neurological disorders in aging.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aging
- Analysis of Variance
- Brain
- Brain Mapping
- Carbon Dioxide
- Cerebrovascular Circulation
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Oxygen
- Reference Values
- Spin Labels
- Statistics, Nonparametric
- Time Factors
- Young Adult
Arterial spin labeling (ASL) magnetic resonance imaging uses arterial blood water as an endogenous tracer to measure cerebral blood flow (CBF). In this review, based on ASL studies in the resting state, we discuss state-of-the-art technical and data processing improvements in ASL, and ASL CBF changes in normal aging, mild cognitive impairment (MCI), Alzheimer's disease (AD), and other types of dementia. We propose that vascular and AD risk factors should be considered when evaluating CBF changes in aging, and that other validated biomarkers should be used as inclusion criteria or covariates when evaluating CBF changes in MCI and AD. With improvements in hardware and experimental design, ASL is proving to be an increasingly promising tool for exploring pathogenetic mechanisms, early detection, monitoring disease progression and pharmacological response, and differential diagnosis of AD.
MeSH Terms
- Aging
- Alzheimer Disease
- Cerebrovascular Circulation
- Humans
- Magnetic Resonance Imaging
- Spin Labels
Keywords
- Aging
- Alzheimer’s disease
- Arterial spin labeling
- Cerebral blood flow
- Magnetic resonance imaging
- Mild cognitive impairment
Three-dimensional Arterial Spin Labeling (ASL) MRI was performed before surgery in a cohort of 146 prospectively enrolled subjects ≥ 70 years old scheduled to undergo elective surgery. We investigated the prospective association between ASL-derived measures of cerebral blood flow (CBF) before surgery with postoperative delirium incidence and severity using whole-brain and globally normalized voxel-wise analysis. We also investigated the cross-sectional association of CBF with patients' baseline performance on specific neuropsychological tests, and with a composite general cognitive performance measure (GCP). Out of 146 subjects, 32 (22%) developed delirium. We found no significant association between global and voxel-wise CBF with delirium incidence or severity. We found the most significant positive associations between CBF of the posterior cingulate and precuneus and the Hopkins Verbal Learning Test - Revised total score, Visual Search and Attention Test (VSAT) score and the GCP composite. VSAT score was also strongly associated with right parietal lobe CBF. ASL can be employed in a large, well-characterized older cohort to examine associations between CBF and age-related cognitive performance. Although ASL CBF measures in regions previously associated with preclinical Alzheimer's Disease were correlated with cognition, they were not found to be indicators of baseline pathology that may increase risk for delirium.
MeSH Terms
- Aged
- Cerebrovascular Circulation
- Cognitive Aging
- Cross-Sectional Studies
- Emergence Delirium
- Humans
- Imaging, Three-Dimensional
- Incidence
- Magnetic Resonance Imaging
- Neuroimaging
- Neuropsychological Tests
- Predictive Value of Tests
- Prospective Studies
- Surveys and Questionnaires
Keywords
- Cerebral blood flow
- aging
- arterial spin labeling
- cognition
- delirium
This paper describes a novel method to improve drug retention in liposomes for the poorly water-soluble (lipophilic) model drug asulacrine (ASL). ASL was loaded in the aqueous phase of liposomes and the effects of aging conditions and drug loading levels on drug retention were investigated using an in vitro bio-relevant drug release test established in this study. The status of intra-liposomal drug was investigated using differential scanning calorimetry (DSC) and cryo-transmission electron microscopy (cryo-TEM). Pharmacokinetics and venous tolerance of the formulations were simultaneously studied in rabbits following one-hour intravenous infusion via the ear vein. The presence of glucose during aging was found to be crucial to accelerate drug precipitation and to stabilize the liposomal membrane with high drug loading (8.9% over 4.5% w/w) as a prerequisite. Although no drug crystals were detected, DSC showed a lower phase-transition peak in the glucose-assisted aged ASL-liposomes, indicating interaction of phospholipids with the sugar. Cryo-TEM revealed more 'coffee bean' like drug precipitate in the ASL-liposomes aged in the glucose solution. In rabbits, these liposomes gave rise to a 1.9 times longer half-life than the fresh liposomes, with no venous irritation observed. Inducing and stabilizing drug precipitation in the liposome cores by aging in the presence of sugar provided an easy approach to improve drug retention in liposomes. The study also highlighted the importance of bio-relevance of in vitro release methods to predict in vivo drug release.
MeSH Terms
- Amsacrine
- Animals
- Antineoplastic Agents
- Calorimetry, Differential Scanning
- Chemical Precipitation
- Chemistry, Pharmaceutical
- Drug Liberation
- Glucose
- Half-Life
- Infusions, Intravenous
- Liposomes
- Microscopy, Electron, Transmission
- Phase Transition
- Rabbits
- Solubility
Keywords
- Active loading
- Aging
- Drug retention
- Glucose
- Liposomes
There is accumulating evidence suggesting that changes in brain perfusion are present long before the clinical symptoms of Alzheimer's disease (AD), perhaps even before amyloid-β accumulation or brain atrophy. This evidence, consistent with the vascular hypothesis of AD, implicates cerebral blood flow (CBF) in the pathogenesis of AD and suggests its utility as a biomarker of preclinical AD. The extended preclinical phase of AD holds particular significance for disease modification, as treatment would likely be most effective in this early asymptomatic stage of disease. This highlights the importance of identifying reliable and accurate biomarkers of AD that can differentiate normal aging from preclinical AD prior to clinical symptom manifestation. Cerebral perfusion, as measured by arterial spin labeling magnetic resonance imaging (ASL-MRI), has been shown to distinguish between normal controls and adults with AD. In addition to demonstrating diagnostic utility, CBF has shown usefulness as a tool for identifying those who are at risk for AD and for predicting subtle cognitive decline and conversion to mild cognitive impairment and AD. Taken together, this evidence not only implicates CBF as a useful biomarker for tracking disease severity and progression, but also suggests that ASL-measured CBF may be useful for identifying candidates for future AD treatment trials, especially in the preclinical, asymptomatic phases of the disease.
MeSH Terms
- Aging
- Alzheimer Disease
- Biomarkers
- Cerebrovascular Circulation
- Genetic Predisposition to Disease
- Humans
- Risk Factors
Keywords
- Alzheimer’s disease
- Arterial spin labeling
- Cerebral blood flow
- Mild cognitive impairment
- Neuroimaging
- Perfusion
To compare the effects of normal growth and longer term use of orthokeratology (ortho-k) on ocular biometric parameters in the anterior segment, including central corneal thickness (CCT), anterior chamber depth (ACD), crystalline lens thickness (CLT), and anterior segment length (ASL). Baseline and six monthly data were retrieved from 78 subjects (aged 7-10 years, with myopia≤4.00D and astigmatism≤1.25D) who had completed a two-year randomized clinical trial using ortho-k for myopia control. They were randomly assigned to wear ortho-k lenses or single-vision spectacles (control). Anterior segment parameters were measured with the Pentacam after cycloplegia. No significant changes in CLT and ASL over time were observed in either group of subjects (37 ortho-k; 38 control). In the control group, CCT remained unchanged during the study period but in the ortho-k group, it was significantly reduced by an average of 0.009mm by the 6-month visit (p<0.001) and remained unchanged thereafter. No significant changes in ACD was found in the ortho-k group but it was significantly increased by an average of 0.04mm (p=0.001) in the control group. CLT nor ASL did not change over time in either control or ortho-k subjects. Although ACD significantly increased in the control subjects and CCT significantly reduced in the first six months of ortho-k lens wear, these changes were small and did not affect the overall ASL.
MeSH Terms
- Aging
- Anterior Eye Segment
- Child
- Female
- Humans
- Longitudinal Studies
- Male
- Myopia
- Orthokeratologic Procedures
- Treatment Outcome
Keywords
- Anterior chamber depth
- Anterior segment length
- Myopia control
- Orthokeratology
The signal intensity obtained by arterial spin labeling (ASL) depends not only on perfusion signal, but also on arterial transit time (ATT). Although ATT has a more significant effect on accurate regional cerebral blood flow (CBF) calculations, the multiple post-labeling delay (PLD) approach is difficult to use in routine examinations. To optimize imaging parameters for labeling duration (LD) and PLD and to confirm their validity in long-labeled pseudo-continuous ASL. The perfusion signal was simulated in four LDs and theoretical signal-to-noise ratio efficiency (SNR ) was calculated. In vivo studies were performed on a 3.0 T magnetic resonance imaging (MRI) scanner and 15 volunteers were categorized into either the young or elderly adult groups. We compared the differences in CBF values with or without ATT correction. Regarding signal simulation, perfusion signal increased with the length of LD. SNR also improved with LD, but SNR plateaued at an LD of 3.0 s. As for the in vivo study, SNR linearly increased along with the LD. The CBF differences with the correction of ATT were larger in the elderly adult group. This trend was most prominent in the longer ATT area in the occipital cortical region. A combination of imaging settings of LD = 3.5 s and PLD = 2.0 s were suggested as optimal imaging parameters for allowing acceptable CBF quantification and sufficient SNR in both young and elderly individuals.
MeSH Terms
- Adult
- Aged
- Aging
- Algorithms
- Blood Flow Velocity
- Cerebral Angiography
- Cerebral Arteries
- Cerebrovascular Circulation
- Female
- Humans
- Image Enhancement
- Image Interpretation, Computer-Assisted
- Magnetic Resonance Angiography
- Male
- Reproducibility of Results
- Sensitivity and Specificity
- Spin Labels
Keywords
- Magnetic resonance imaging (MRI)
- arterial spin labeling (ASL)
- arterial transit time (ATT)
- cerebral blood flow
- perfusion
Vascular compliance (VC) is an important marker for a number of cardiovascular diseases and dementia, which is typically assessed in the central and peripheral arteries indirectly by quantifying pulse wave velocity (PWV), and/or pulse pressure waveform. To date, very few methods are available for the quantification of intracranial VC. In the present study, a novel MRI technique for in-vivo assessment of intracranial VC was introduced, where dynamic arterial spin labeling (ASL) scans were synchronized with the systolic and diastolic phases of the cardiac cycle. VC is defined as the ratio of change in arterial cerebral blood volume (ΔCBV) and change in arterial pressure (ΔBP). Intracranial VC was assessed in different vascular components using the proposed dynamic ASL method. Our results show that VC mainly occurs in large arteries, and gradually decreases in small arteries and arterioles. The comparison of intracranial VC between young and elderly subjects shows that aging is accompanied by a reduction of intracranial VC, in good agreement with the literature. Furthermore, a positive association between intracranial VC and cerebral perfusion measured using pseudo-continuous ASL with 3D GRASE MRI was observed independent of aging effects, suggesting loss of VC is associated with a decline in perfusion. Finally, a significant positive correlation between intracranial and central (aortic arch) VC was observed using an ungated phase-contrast 1D projection PWV technique. The proposed dynamic ASL method offers a promising approach for assessing intracranial VC in a range of cardiovascular diseases and dementia.
MeSH Terms
- Adult
- Arterial Pressure
- Arteries
- Arterioles
- Brain
- Compliance
- Electrocardiography
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Pulse Wave Analysis
- Spin Labels
- Vascular Capacitance
- Young Adult
Keywords
- Aging
- Cardiovascular diseases
- Cerebral perfusion
- Dynamic arterial spin labeling
- Intracranial vascular compliance
- Pulse wave velocity
We assessed changes in the position of the lens with aging in a general population. The population-based Central India Eye and Medical Study included 4711 subjects. As part of an ophthalmic examination, anterior segment length (ASL) was measured sonographically and calculated as anterior chamber depth plus lens thickness. Subjects with nuclear cataract grades 5 or more (43.9% of the sample) were excluded. The study included 2468 subjects (1176 [47.6%] men) with a mean age of 41.2 ± 8.5 years (range, 30-78 years) and mean axial length of 22.68 ± 0.81 mm (range, 19.89-31.02 mm). In multivariate analysis, longer ASL was associated with older age (P = 0.04; correlation coefficient B, 0.002; 95% confidence interval [CI], 0.000, 0.005) after adjusting for male sex (P < 0.001), longer axial length (P < 0.001), higher degree of nuclear cataract (P = 0.001), and higher body mass index (P = 0.02). Greater lens thickness was associated with older age (P < 0.001; B, 0.009; 95% CI, 0.007, 0.0011) after adjusting for male sex (P < 0.001), shallower anterior chamber depth (P < 0.001), and higher degree of nuclear cataract (P < 0.001). Deeper anterior chamber depth was associated with younger age (P < 0.001; B, -0.007; 95% CI, -0.008, -0.005) after adjusting for male sex (P < 0.001), thinner lens thickness (P < 0.001), and longer axial length (P < 0.001). Combining both analyses revealed that for each year increase in age, lens thickness increased by 0.009 mm, anterior chamber depth decreased by 0.007 mm, the posterior lens pole moved backward by 0.002 mm, and the lens center moved forward by 0.0025 mm. Increasing age before the development of cataract is associated with a slight forward movement of the lens center, adding to the lens paradox.
MeSH Terms
- Adult
- Aged
- Aging
- Anterior Chamber
- Biometry
- Cataract
- Cornea
- Corneal Pachymetry
- Cross-Sectional Studies
- Female
- Humans
- India
- Lens, Crystalline
- Male
- Microscopy, Acoustic
- Middle Aged
- Morbidity
- Population Surveillance
- Refractive Errors
Blood oxygenation-level dependent (BOLD) magnetic resonance imaging signal changes in response to stimuli have been used to evaluate age-related changes in neuronal activity. Contradictory results from these types of experiments have been attributed to differences in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2 ). To clarify the effects of these physiological parameters, we investigated the effect of age on baseline CBF and CMRO2 . Twenty young (mean ± sd age, 28 ± 3 years), and 45 older subjects (66 ± 4 years) were investigated. A dual-echo pseudocontinuous arterial spin labeling (ASL) sequence was performed during normocapnic, hypercapnic, and hyperoxic breathing challenges. Whole brain and regional gray matter values of CBF, ASL cerebrovascular reactivity (CVR), BOLD CVR, oxygen extraction fraction (OEF), and CMRO2 were calculated. Whole brain CBF was 49 ± 14 and 40 ± 9 ml/100 g/min in young and older subjects respectively (P < 0.05). Age-related differences in CBF decreased to the point of nonsignificance (B=-4.1, SE=3.8) when EtCO2 was added as a confounder. BOLD CVR was lower in the whole brain, in the frontal, in the temporal, and in the occipital of the older subjects (P<0.05). Whole brain OEF was 43 ± 8% in the young and 39 ± 6% in the older subjects (P = 0.066). Whole brain CMRO2 was 181 ± 60 and 133 ± 43 µmol/100 g/min in young and older subjects, respectively (P<0.01). Age-related differences in CBF could potentially be explained by differences in EtCO2 . Regional CMRO2 was lower in older subjects. BOLD studies should take this into account when investigating age-related changes in neuronal activity.
MeSH Terms
- Adult
- Aged
- Aging
- Brain
- Cerebral Cortex
- Cerebrovascular Circulation
- Female
- Gray Matter
- Hemodynamics
- Humans
- Hypercapnia
- Hyperoxia
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Oxygen
- Oxygen Consumption
- Respiratory Function Tests
- Spin Labels
- Young Adult
Keywords
- ageing
- calibrated magnetic resonance imaging
- cerebral blood flow
- cerebral metabolic rate of oxygen
White matter hyperintensities (WMHs) are common with age, grow over time, and are associated with cognitive and motor impairments. Mechanisms underlying WMH growth are unclear. We aimed to determine the presence and extent of decreased normal appearing white matter (NAWM) cerebral blood flow (CBF) surrounding WMHs to identify 'WM at risk', or the WMH CBF penumbra. We aimed to further validate cross-sectional finding by determining whether the baseline WMH penumbra CBF predicts the development of new WMHs at follow-up. Sixty-one cognitively intact elderly subjects received 3 T MPRAGE, FLAIR, and pulsed arterial spin labeling (PASL). Twenty-four subjects returned for follow-up MRI. The inter-scan interval was 18 months. A NAWM layer mask, comprised of fifteen layers, 1 mm thick each surrounding WMHs, was generated for periventricular (PVWMH) and deep (DWMH) WMHs. Mean CBF for each layer was computed. New WMH and persistent NAWM voxels for each penumbra layer were defined from follow-up MRI. CBF in the area surrounding WMHs was significantly lower than the total brain NAWM, extending approximately 12 mm from both the established PVWMH and DWMH. Voxels with new WMH at follow-up had significantly lower baseline CBF than voxels that maintained NAWM, suggesting that baseline CBF can predict the development of new WMHs over time. A CBF penumbra exists surrounding WMHs, which is associated with future WMH expansion. ASL MRI can be used to monitor interventions to increase white matter blood flow for the prevention of further WM damage and its cognitive and motor consequences.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Cerebrovascular Circulation
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Spin Labels
- White Matter
Keywords
- Arterial spin labeling (ASL)
- CASL, continuous arterial spin labeling
- CBF, cerebral blood flow
- Cerebral blood flow (CBF) penumbra
- Cognitive aging
- DWMH, deep white matter hyperintensity
- M0, the initial ASL datasets
- NAWM L1, normal appearing white matter layer 1
- NAWM L15, normal appearing white matter layer 15
- NAWM, normal appearing white matter
- PASL, pulsed arterial spin labeling
- PCASL, pseudo-continuous arterial spin labeling
- PVWMH, periventricular white matter hyperintensity
- Vascular dementia
- WMH, white matter hyperintensity
- White matter hyperintensity (WMH)
Cerebral blood flow (CBF) is a physiological correlate of brain function and metabolism and as such an essential parameter for investigating how aging and disease affect the brain. Arterial spin labeling (ASL) is an fMRI method that provides absolute measurement of CBF non-invasively and with higher spatial resolution than non-MRI methods. However, application of ASL in older populations is hampered by partial volume effects (PVE) and tissue dependent changes in CBF. We have developed a tissue-specific ASL method (ts-ASL) that provides `flow density' measures by quantifying CBF for each tissue separately and independently of tissue content. Using simulated functional and structural images, we investigated the effects of brain atrophy and random noise on the SNR of GM CBF measured with conventional and ts-ASL. Results showed that: (1) For all noise levels, the SNR of ts-ASL was higher. For example, for a random Gaussian noise with standard deviation σ = 4, the SNR of GM CBF obtained with ts-ASL was ~3 times higher than the SNR of the conventional method. (2) In contrast to conventional ASL, which was substantially affected by brain atrophy, ts-ASL was virtually independent of it. (3) The sensitivity of ts-ASL for detecting focal changes in CBF (ΔCBF) in the presence of atrophy and noise was also higher compared to the conventional method. In hippocampus, for 15% atrophy and Gaussian noise with σ = 4, conventional and ts-ASL retrieved 73% and 90% of the modeled ΔCBF, respectively. Taken together, these results indicate that ts-ASL may be better suited for measuring CBF in the presence of atrophy and random noise, both of which are expected to increase with aging and disease.
MeSH Terms
- Aged
- Aging
- Atrophy
- Brain Diseases
- Cerebrovascular Circulation
- Hippocampus
- Humans
- Magnetic Resonance Imaging
- Organ Specificity
- Signal-To-Noise Ratio
- Spin Labels
Obesity has dramatically increased in prevalence, making it essential to understand its accompanying metabolic changes. Modeling diet-induced obesity in Drosophila melanogaster (fruit flies), we elucidated transcriptional and metabolic changes in w (1118) flies on a high-fat diet (HFD). Mass spectrometry-based metabolomics revealed altered fatty acid, amino acid, and carbohydrate metabolism with HFD. Microarray analysis uncovered transcriptional changes in nitrogen metabolism, including CG9510, homolog of human argininosuccinate lyase (ASL). CG9510 knockdown in flies phenocopied traits observed with HFD, namely increased triglyceride levels and decreased cold tolerance. Restoration of CG9510 expression ameliorated observed negative consequences of HFD. Metabolomic analysis of CG9510 knockdown flies confirmed functional similarity to ASL, regulating the balance of carbon and nitrogen metabolism. In summary, we found that HFD suppresses CG9510 expression, a gene required for proper triglyceride storage and stress tolerance. These results draw an important link between regulation of amino acid metabolism and the response to diet-induced obesity.
Keywords
- ASL, argininosuccinate lyase
- AcCoA, acetyl-coenzyme A
- Argininosuccinate lyase
- BCAA, branch chain amino acid
- CAFE, capillary feeder
- EASE, Expression Analysis Systematic Explorer (DAVID analysis)
- FAME, fatty acid methyl ester
- Fdr, false discovery rate
- GC/MS, gas chromatography/mass spectrometry
- HFD, high-fat Diet
- Lifespan
- MeOH, methanol
- Metabolism
- Obesity
- PCR, polymerase chain reaction
- RT-PCR, reverse-transcriptase PCR
- TBDMS, tert-butyldimethylsilyl
- TCA, tricarboxylic acid
- TG, triglyceride
- TMS, trimethylsilyl
- Triglyceride
- VDRC, Vienna Drosophila RNAi Center
- arm-GAL4, armadillo-GAL4
- da-GAL4, daughterless-Gal4
- w1118, white-1118
Functional magnetic resonance imaging (fMRI) studies of cognitive aging have generally compared the amplitude and extent of blood oxygen level-dependent (BOLD) signal increases evoked by a task in older and younger groups. BOLD is thus used as a direct index of neuronal activation and it is assumed that the relationship between neuronal activity and the hemodynamic response is unchanged across the lifespan. However, even in healthy aging, differences in vascular and metabolic function have been observed that could affect the coupling between neuronal activity and the BOLD signal. Here we use a calibrated fMRI method to explore vascular and metabolic changes that might bias such BOLD comparisons. Though BOLD signal changes evoked by a cognitive task were found to be similar between a group of younger and older adults (e.g., 0.50 ± 0.04% vs. 0.50 ± 0.05% in right frontal areas), comparison of BOLD and arterial spin labelling (ASL) responses elicited in the same set of structures by a controlled global hypercapnic manipulation revealed significant differences between the 2 groups. Older adults were found to have lower responses in BOLD and flow responses to hypercapnia (e.g., 1.48 ± 0.07% vs. 1.01 ± 0.06% over gray matter for BOLD and 24.92 ± 1.37% vs. 20.67 ± 2.58% for blood flow), and a generally lower maximal BOLD response M (5.76 ± 0.2% vs. 5.00 ± 0.3%). This suggests that a given BOLD response in the elderly might represent a larger change in neuronal activity than the same BOLD response in a younger cohort. The results of this study highlight the importance of ancillary measures such as ASL for the correct interpretation of BOLD responses when fMRI responses are compared across populations who might exhibit differences in vascular physiology.
MeSH Terms
- Adult
- Aging
- Blood Flow Velocity
- Brain
- Cerebrovascular Circulation
- Cognition
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Oxygen Consumption
The purpose of this study was to evaluate if non-invasive Arterial Spin Labeling MR imaging can be used to assess changes in brain perfusion with age which reflect neonatal brain development. For this purpose regional perfusion values obtained with ASL MR imaging were evaluated as a function of postmenstrual age. Pulsed ASL imaging was performed in 33 neonates with a postmenstrual age from 30 to 53 weeks. Whole brain cerebral blood flow (wbCBF), CBF in the basal ganglia and thalamus (BGT-CBF), in the occipital cortex (OC-CBF) and the frontal cortex (FC-CBF) were measured. Regional CBF values were expressed quantitatively (in ml/100 g min) and relative as a percentage of the wbCBF. Mean wbCBF increased significantly from 7±2 ml/100 g min (mean±sd) at 31±2 weeks postmenstrual age to 12±3 ml/100 g min at term-equivalent age (TEA) and 29±9 ml/100 g min at 52±1 weeks postmenstrual age. Relative regional CBF was highest in the BGT at all time-points. Relative OC-and FC-CBF increased significantly from 31±2 weeks postmentrual age to TEA. A significant difference in relative BGT-CBF and OC-CBF was shown between infants at 31±2 weeks postmenstrual age and infants scanned at 52±1 weeks postmenstrual age. Relative perfusion in the BGT measured at TEA was significant different compared to 52±1 weeks postmenstrual age. In conclusion, regional differences in CBF and changes with postmenstrual age could be detected with ASL in neonates. This suggests that ASL can be used as a non-invasive tool to investigate brain maturation in neonates.
MeSH Terms
- Aging
- Brain
- Cerebrovascular Circulation
- Female
- Humans
- Infant
- Infant, Newborn
- Magnetic Resonance Angiography
- Male
- Reproducibility of Results
- Sensitivity and Specificity
- Spin Labels
Despite advances in the treatment of patients with human immunodeficiency virus (HIV), HIV-associated neurocognitive disorder occurs in 15-50% of HIV-infected individuals, and may become more apparent as ageing advances. In the present study we investigated regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of glucose uptake (rCMRglc) in medically and psychiatrically stable HIV-1-infected participants in two age-groups. Positron emission tomography (PET) and magnetic resonance imaging (MRI)-based arterial spin labeling (ASL) were used to measure rCMRglc and rCBF, respectively, in 35 HIV-infected participants and 37 HIV-negative matched controls. All participants were currently asymptomatic with undetectable HIV-1 viral loads, without medical or psychiatric comorbidity, alcohol or substance misuse, stable on medication for at least 6 months before enrolment in the study. We found significant age effects on both ASL and PET with reduced rCBF and rCMRglc in related frontal brain regions, and consistent, although small, reductions in rCBF and rCMRglc in the anterior cingulate cortex (ACC) in HIV, a finding of potential clinical significance. There was no significant interaction between HIV status and the ageing process, and no significant HIV-related changes elsewhere in the brain on PET or ASL. This is the first paper to combine evidence from ASL and PET method in HIV participants. These finding provide evidence of crossvalidity between the two techniques, both in ageing and a clinical condition (HIV).
MeSH Terms
- Adult
- Affect
- Aged
- Aging
- Antiretroviral Therapy, Highly Active
- Asymptomatic Diseases
- Brain
- Brain Mapping
- Cerebrovascular Circulation
- Corpus Striatum
- Fluorine Radioisotopes
- Fluorodeoxyglucose F18
- HIV Infections
- HIV-1
- Humans
- Intelligence Tests
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Multimodal Imaging
- Neuropsychological Tests
- Positron-Emission Tomography
- Radiopharmaceuticals
- Spin Labels
- Young Adult
Keywords
- ASL
- HIV
- PET
- ageing
- glucose uptake
- rCBF
We examined the correlation between brain perfusion and age using pulsed arterial spin-labeling (ASL) magnetic resonance images (MRI) in a large number of healthy children. We collected data on brain structural and ASL perfusion MRI in 202 healthy children aged 5-18 years. Structural MRI data were segmented and normalized, applying a voxel-based morphometric analysis. Perfusion MRI was normalized using the normalization parameter of the corresponding structural MRI. We calculated brain perfusion with an adjustment for gray matter density (BP-GMD) by dividing normalized ASL MRI by normalized gray matter segments in 22 regions. Next, we analyzed the correlation between BP-GMD and age in each region by estimating linear, quadratic, and cubic polynomial functions, using the Akaike information criterion. The correlation between BP-GMD and age showed an inverted U shape followed by a U-shaped trajectory in most regions. In addition, age at which BP-GMD was highest was different among the lobes and gray matter regions, and the BP-GMD association with age increased from the occipital to the frontal lobe via the temporal and parietal lobes. Our results indicate that higher order association cortices mature after the lower order cortices, and may help clarify the mechanisms of normal brain maturation from the viewpoint of brain perfusion.
MeSH Terms
- Adolescent
- Aging
- Asian Continental Ancestry Group
- Brain
- Cerebrovascular Circulation
- Child
- Data Interpretation, Statistical
- Female
- Frontal Lobe
- Humans
- Image Processing, Computer-Assisted
- Magnetic Resonance Imaging
- Male
- Occipital Lobe
- Parietal Lobe
- Reference Values
- Temporal Lobe
We have analyzed hospitalizations of older people (> 64) from 2002 to 2005. Patients, discharges and stay in hospital have increased, the variation has been statistically significant. We have noticed the same trend about the rehospitalizations. Patients and discharges coming from ASL 5 and zone 4 have decreased in relation with all the elderly people. The reduction of stay in hospital and the decrease of rehospitalizations have been statistically significant.
MeSH Terms
- Age Factors
- Aged
- Aged, 80 and over
- Data Interpretation, Statistical
- Hospitalization
- Hospitals, University
- Humans
- Italy
- Length of Stay
- Life Expectancy
- National Health Programs
- Patient Readmission
- Time Factors
Craniosynostosis is the premature fusion of the calvarial sutures and is associated with aesthetic impairment and secondary damage to brain growth. Associated neurological injuries can result from increased intracranial pressure (ICP) and abnormal cerebral blood flow (CBF). Arterial spin-labeling (ASL) MRI was used to assess regional CBF in developing rabbits with early-onset coronal suture synostosis (EOCS) and age-matched wild-type controls (WT). Rabbits were subjected to ASL MRI at or near 10, 25, or 42 days of age. Differences in regional CBF were assessed using one-way ANOVA. CBF was similar in WT and EOCS rabbits with the exception of the peridural surfaces in EOCS rabbits at 25 days of age. A twofold increase in peridural CBF at 25 days of age coincides with a transient increase in ICP. By 42 days of age, CBF in peridural surfaces had decreased.
MeSH Terms
- Aging
- Analysis of Variance
- Animals
- Brain
- Cerebrovascular Circulation
- Craniosynostoses
- Dura Mater
- Hyperemia
- Magnetic Resonance Imaging
- Rabbits
Arterial spin labeling (ASL) is a safe, noninvasive imaging method for evaluating cerebral blood flow (rCBF). The purpose of this article is to present ASL imaging features of 38 elderly cognitively normals (CN) with their rCBF values and an averaged profile of targeted anatomic regions rCBF values. Thirty-eight CN underwent MR imaging especially ASL with voxel morphometric techniques fusing the MR anatomical and ASL images to a standard reference brain (colin27). The ASL images were fused to echo planar images, which were then coregistered to high-resolution anatomical SPGR images. rCBF was calculated per region of interest using a modified continuous arterial spin labeling (CASL) convolutional method. Anatomical regions were selected and identified by the Talairach atlas in SPM2. We identified areas of decreased and increased perfusion (compared to the averaged rCBF of all 38 CN) corresponding to decreased and increased quantified rCBF. The most common sites for decreased perfusion were precuneus (53%), superior temporal (48%), and orbitofrontal (37%), and for increased perfusion the caudate (39%), posterior cingulate (34%), anterior cingulate (32%), and amygdala (32%). There are regional variations in rCBF both increased and decreased with the posterior cingulate and precuneus cortex showing the highest averaged values and signal intensity (bright spots). These variations represent the normal profile of a CN elderly brain, with higher perfusion in areas associated with cognition, memory, and behavior. It is necessary to understand these normal variations in order to determine if there are perfusion changes in ASL detected in neurodegenerative disorders such as Alzheimer's disease.
MeSH Terms
- Aged, 80 and over
- Aging
- Brain
- Brain Mapping
- Cerebrovascular Circulation
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Neurodegenerative Diseases
- Signal Processing, Computer-Assisted
- Spin Labels
Cerebral blood flow (CBF) alterations after asphyxial cardiac arrest (CA) are not defined in developmental animal models or humans. We characterized regional and temporal changes in CBF from 5 to 150 mins after asphyxial CA of increasing duration (8.5, 9, 12 min) in postnatal day (PND) 17 rats using the noninvasive method of arterial spin-labeled magnetic resonance imaging (ASL-MRI). We also assessed blood-brain barrier (BBB) permeability, and evaluated the relationship between CBF and mean arterial pressure after resuscitation. After all durations of asphyxia CBF alterations were region dependent. After 8.5- and 9-min asphyxia, intense subcortical hyperemia at 5 min was followed by return of CBF to baseline values by 10 mins. After 12-min asphyxia, hyperemia was absent and hypoperfusion reached a nadir of 38% to 65% of baselines with the lowest values in the cortex. BBB was impermeable to gadoteridol 150 mins after CA. CBF in the 12-min CA group was blood pressure passive at 60 min assessed via infusion of epinephrine. ASL-MRI assessment of CBF after asphyxial CA in PND 17 rats reveals marked duration and region-specific reperfusion patterns and identifies possible new therapeutic targets.
MeSH Terms
- Aging
- Animals
- Asphyxia
- Blood Pressure
- Blood-Brain Barrier
- Body Weight
- Cerebrovascular Circulation
- Heart Arrest
- Magnetic Resonance Imaging
- Rats
- Rats, Sprague-Dawley
To evaluate anterior segment alterations with age and during accommodation in different age groups. Department of Ophthalmology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary. Fifty-three subjects (101 normal eyes) were enrolled in this study and divided into 3 age groups: younger than 30 years (Group 1), between 31 years and 44 years (Group 2), and older than 45 years (Group 3). The total amplitude of accommodation was determined with a defocusing technique, and anterior segment measurements were performed by partial coherence interferometry. Group 1 comprised 32 eyes; Group 2, 37 eyes; and Group 3, 32 eyes. The total amplitude of accommodation decreased with age (P<.0001). With the target position at infinity, the lens thickness (LT) and anterior segment length (ASL) increased and the anterior chamber depth (ACD) decreased significantly with age (P<.0001). During accommodation in the youngest group, the mean change in LT was 36.3 mum/diopter (D) and in ACD, -26.7 mum/D. The mean accommodation-induced ACD change was -0.08 mm /- 0.06 (SD) in Group 1, -0.064 /- 0.087 mm in Group 2, and -0.03 /- 0.06 mm in Group 3 (P = .0004). The mean LT change during near fixation was 0.109 /- 0.063 mm in Group 1, 0.103 /- 0.136 mm in Group 2, and 0.006 /- 0.05 mm in Group 3 (P<.0001). The mean ASL change during accommodation was 0.029 /- 0.037 mm, 0.039 /- 0.114 mm, and -0.023 /- 0.051, respectively (P<.0001). In addition to forward movement of the anterior lens surface with age, the posterior surface moved backward. Alterations in LT and ACD sufficient for a unit of refractive power change during accommodation might be smaller than previously thought. Anterior shifting of the lens may also participate in the accommodative response.
MeSH Terms
- Accommodation, Ocular
- Adolescent
- Adult
- Aged
- Aging
- Anterior Eye Segment
- Biometry
- Diagnostic Techniques, Ophthalmological
- Female
- Humans
- Interferometry
- Lens, Crystalline
- Light
- Male
- Middle Aged
- Prospective Studies
Functional magnetic resonance imaging (fMRI) studies of the medial temporal lobe have primarily made use of the blood oxygenation level dependent (BOLD) response to neural activity. The interpretation of the BOLD signal as a measure of medial temporal lobe function can be complicated, however, by changes in the cerebrovascular system that can occur with both normal aging and age-related diseases, such as Alzheimer's disease. Quantitative measures of the functional cerebral blood flow (CBF) response offer a useful complement to BOLD measures and have been shown to aid in the interpretation of fMRI studies. Despite these potential advantages, the application of ASL to fMRI studies of cognitive tasks and at-risk populations has been limited. In this study, we demonstrate the application of ASL fMRI to obtain measures of the CBF and BOLD responses to the encoding of natural scenes in healthy young (mean 25 years) and elderly (mean 74 years) adults. The percent CBF increase in the medial temporal lobe was significantly higher in the older adults, whereas the CBF levels during baseline and task conditions and during a separate resting-state scan were significantly lower in the older group. The older adults also showed slightly higher values for the BOLD response amplitude and the absolute change in CBF, but the age group differences were not significant. The percent CBF and BOLD responses are consistent with an age-related increase in the cerebral metabolic rate of oxygen metabolism (CMRO(2)) response to memory encoding.
MeSH Terms
- Adult
- Aged
- Aging
- Brain
- Cerebrovascular Circulation
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Memory
- Oxygen
Normal aging is associated with a decline in pulmonary function and efficiency of gas exchange, although the effects on the spatial distribution of pulmonary perfusion are poorly understood. We hypothesized that spatial pulmonary perfusion heterogeneity would increase with increasing age. Fifty-six healthy, nonsmoking subjects (ages 21-76 yr) underwent magnetic resonance imaging with arterial spin labeling (ASL) using a Vision 1.5-T whole body scanner (Siemens Medical Systems, Erlangen, Germany). ASL uses a magnetically tagged bolus to generate perfusion maps where signal intensity is proportional to regional pulmonary perfusion. The spatial heterogeneity of pulmonary blood flow was quantified by the relative dispersion (RD = SD/mean, a global index of heterogeneity) of signal intensity for voxels within the right lung and by the fractal dimension (D(s)). There were no significant sex differences for RD (P = 0.81) or D(s) (P = 0.43) when age was considered as a covariate. RD increased significantly with increasing age by approximately 0.1/decade until age 50-59 yr, and there was a significant positive relationship between RD and age (R = 0.48, P < 0.0005) and height (R = 0.39, P < 0.01), but not body mass index (R = 0.07, P = 0.67). Age and height combined in a multiple regression were significantly related to RD (R = 0.66, P < 0.0001). There was no significant relationship between RD and spirometry or arterial oxygen saturation. D(s) was not related to age, height, spirometry, or arterial oxygen saturation. The lack of relationship between age and D(s) argues against an intrinsic alteration in the pulmonary vascular branching with age as being responsible for the observed increase in global spatial perfusion heterogeneity measured by the RD.
MeSH Terms
- Adult
- Aged
- Aging
- Female
- Fractals
- Humans
- Image Processing, Computer-Assisted
- Linear Models
- Lung
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Pulmonary Circulation
- Reference Values
- Research Design
- Respiratory Function Tests
- Respiratory Physiological Phenomena
- Spin Labels
To study the normal dependence of cerebral perfusion changes on age, to measure values of perfusion early in life, and to create a reference dataset. Perfusion maps were collected from a total of 44 healthy subjects (from four to 78 years old) using the arterial spin labeling (ASL) technique. The population was retrospectively divided into three age groups: children, teenagers, and adults. For each group, mean values of cerebral blood flow (CBF) were calculated in gray matter (GM) and white matter (WM). Results were compared across the three different age groups. CBF values decreased with age (97 /-5 mL/100 g/minute in GM and 26 /-1 mL/100 g/minute in WM for the children, GM 79 /-3 mL/100 g/minute and WM 22 /-1 mL/100 g/minute for the teenagers, and GM 58 /-4 mL/100 g/minute, WM 20 /-1 mL/100 g/minute for the adults). The quantitative results suggest a rapid drop, rather than a gradual decrease, in cerebral perfusion between children and adult subjects, especially in the GM. This step in CBF occurs during adolescence, at approximately the 16th year of age. ASL is a practical and quantitative technique suitable for perfusion measurement in children as well as adults. Perfusion measurements with ASL appear sensitive to neurophysiological changes occurring during brain maturation.
MeSH Terms
- Adolescent
- Adult
- Aged
- Aging
- Cerebrovascular Circulation
- Child
- Child, Preschool
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Reference Values
- Spin Labels
Currently, different cerebral neuroimaging methods are being applied to varying questions in the diagnosis of dementia. In patients with manifest Alzheimer's disease a reduction of cortical perfusion and metabolism in temporal and temporoparietal regions has been demonstrated when compared to healthy controls on a diversity of memory tasks. Since differing levels of performance and varying degrees of cortical atrophy may influence functional results considerably, an understanding of the processes associated with normal ageing is perceived as prerequisite for studies applying functional neuroimaging. The integration of knowledge concerning neuropsychological and neurobiological alterations associated with healthy ageing allows hypotheses for the differentiation of pathological ageing processes to be phrased. In this connection non-invasive methods such as fMRI and ASL are of increasing importance.
MeSH Terms
- Adult
- Age Factors
- Aged
- Aged, 80 and over
- Aging
- Alzheimer Disease
- Brain
- Cerebrovascular Circulation
- Clinical Trials as Topic
- Dementia
- Diagnosis, Differential
- Glucose
- Humans
- Magnetic Resonance Imaging
- Memory Disorders
- Middle Aged
- Risk Factors
- Sensitivity and Specificity
- Time Factors
The expression of two genes, coding for argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL), enzymes which synthesize arginine, was studied by Northern analysis in various tissues of fetal rats. The highest expression of both genes was seen in the small intestine, liver and kidney of the fetus. The developmental expression was observed in the kidney where both mRNA levels remained low during the fetal period and they increased concomitantly in both kidney and liver throughout the perinatal life, suggesting that the aptitude to synthesize arginine appeared and developed within the same period in both organs. This developmental activation of the ASS and ASL genes expression corresponded, at least in part, to a transcriptional mechanism in both tissues, as measured by run-on assay. Bilateral adrenalectomy showed that glucocorticoids did not appear to control the developmental expression of both genes in the kidney, in contrast to the situation observed in the liver.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Arginine
- Argininosuccinate Lyase
- Argininosuccinate Synthase
- Blotting, Northern
- Gene Expression
- Glucocorticoids
- Intestines
- Kidney
- Liver
- RNA, Messenger
- Rats
- Rats, Wistar
- Tissue Distribution
- Transcription, Genetic
Weaning is associated with increased intestinal metabolism of glutamine and arginine as well as elevated plasma concentrations of cortisol (the major circulating glucocorticoid) in pigs. The objective of this study was to determine if cortisol plays an important role in mediating the enhanced amino acid metabolism in enterocytes of weaned pigs by administering RU486 (a glucocorticoid receptor antagonist). Eighteen 21-d-old pigs were randomly assigned to three groups of six. Two of these groups received intramuscular injections of 0 or 10 mg RU486 per kg body weight 5 min before and 24 and 72 h after weaning to a corn-soybean meal-based diet. The third group was allowed to suckle freely from sows. When the pigs were 29 d old, jugular venous blood was obtained and pigs were killed for preparation of jejunal enterocytes. The activities of arginase, argininosuccinate synthase (ASS), argininosuccinate lyase (ASL) and pyrroline-5-carboxylate (P5C) synthase were measured. For metabolic studies, cells were incubated for 0 or 30 min at 37 degrees C in 2 mL of Krebs-bicarbonate buffer (pH 7.4) containing 0 or 2 mmol/L L-[U-14C]arginine or 2 mmol/L L-[U-14C]glutamine. In comparison with suckling pigs, weaning resulted in increases in the following: 1) the activities of arginase, ASS, ASL and P5C synthase, 2) the metabolism of arginine to CO2, proline and ornithine, and 3) the conversion of glutamine to ornithine, citrulline and CO2. The effects of the administration of RU486 were as follows: 1) attenuation of the increase in arginase activity and the production of ornithine from arginine, 2) abolition of the induction of ASL and P5C synthase, and 3) prevention of the increase in glutamine metabolism and the production of proline and CO2 from arginine in enterocytes of weaned pigs. These data suggest that glucocorticoids play an essential role in mediating the enhanced intestinal degradation of arginine and glutamine during weaning.
MeSH Terms
- Aging
- Ammonia
- Animals
- Arginase
- Arginine
- Argininosuccinate Lyase
- Argininosuccinate Synthase
- Carbon Dioxide
- Cells, Cultured
- DNA
- Enzyme Induction
- Female
- Glucocorticoids
- Glutamine
- Hydrocortisone
- Jejunum
- Male
- Mifepristone
- Ornithine
- Proline
- Receptors, Glucocorticoid
- Swine
- Urea
- Weaning
Chicken argininosuccinate lyase (ASL)/delta-crystallin, a lens enzyme-crystallin, is encoded in two linked genes (delta 1 and delta 2); only the delta 2 polypeptide contains ASL activity. Here we have quantified delta 1- and delta 2-crystallin mRNA in the lens, cornea, neural retina, heart, and brain at different stages of embryonic development and in 1-wk-old and 1-yr-old chickens by the polymerase chain reaction using internal delta 1 and delta 2 RNA standards. The delta 1/delta 2 mRNA ratio differed for every tissue and was regulated during development. In the embryo there was more delta 1 than delta 2 mRNA in the lens (50-100 times), cornea (3-4 times), and neural retina (2-20 times), about equal amounts of delta 1 and delta 2 mRNA in the heart, and more delta 2 mRNA in the brain (15 times). delta 1-Crystallin mRNA differentially decreased in every tissue after hatching; by contrast, the delta 2 mRNA remained about the same except for the lens, where it decreased 50-fold between 1 wk and 1 yr after hatching. In the 1-yr-old chicken, the delta 2/delta 1 mRNA ratios were 7 in the lens, 175 in the cornea, 22 in the neural retina, 107 in the heart, and 136 in the brain, indicating that delta 2-crystallin is strongly favored in all adult tissues of the chicken. The excess of delta 1 to delta 2 mRNA in the embryonic lens, cornea, and neural retina is intriguing, and suggests some connection with developing transparent eye tissues. Finally, we raise the possibility that expression of both delta-crystallin genes may create tetrameric ASL isoenzymes (perhaps with different specific activities). The unexpected predominance of delta 2 mRNA in the 1-yr-old lens suggests that both the enzymatic and refractive functions of ASL/delta-crystallin are operative and spatially separated, with the enzymatic role present in the cortical fibers and the refractive role in the center of the lens.
MeSH Terms
- Aging
- Animals
- Argininosuccinate Lyase
- Base Sequence
- Brain
- Brain Chemistry
- Chick Embryo
- Chickens
- Cornea
- Crystallins
- DNA
- Embryonic and Fetal Development
- Gene Expression
- Genes
- Heart
- Lens, Crystalline
- Molecular Sequence Data
- Myocardium
- Polymerase Chain Reaction
- RNA, Messenger
- Retina