It is increasingly recognized that obesity is a risk factor for microvascular disease, involving both structural and functional changes in the microvasculature. This review aims to describe how ...obesity impacts the microvasculature of a variety of tissues, including visceral adipose tissue, skeletal muscle, heart, brain, kidneys, and lungs. These changes involve endothelial dysfunction, which in turn (i) impacts control of vascular tone, (ii) contributes to development of microvascular insulin resistance, (iii) alters secretion of paracrine factors like nitric oxide and endothelin, but (iv) also influences vascular structure and perivascular inflammation. In concert, these changes impair organ perfusion and organ function thereby contributing to altered release and clearance of neurohumoral factors, such as adipokines and inflammatory cytokines. Global microvascular dysfunction in obese subjects is therefore a common pathway that not only explains exercise-intolerance but also predisposes to development of chronic kidney disease, microvascular dementia, coronary microvascular angina, heart failure with preserved ejection fraction, chronic obstructive pulmonary disease, and pulmonary hypertension.
Dynamic exercise elicits fluctuations in blood pressure (BP) and cerebral blood flow (CBF). This study investigated responses in BP and CBF during cycling exercise and post-exercise hypotension (PEH) ...using positron emission tomography (PET). CBF was measured using oxygen-15-labeled water (H
O) and PET in 11 human subjects at rest (Rest), at the onset of exercise (Ex1), later in the exercise (Ex2), and during PEH. Global CBF significantly increased by 13% at Ex1 compared with Rest, but was unchanged at Ex2 and during PEH. Compared with at Rest, regional CBF (rCBF) increased at Ex1 (20~42%) in the cerebellar vermis, sensorimotor cortex for the bilateral legs (M1
and S1
), insular cortex and brain stem, but increased at Ex2 (28~31%) only in the vermis and M1
and S1
. During PEH, rCBF decreased compared with Rest (8~13%) in the cerebellum, temporal gyrus, piriform lobe, thalamus and pons. The areas showing correlations between rCBF and mean BP during exercise and PEH were consistent with the central autonomic network, including the brain stem, cerebellum, and hypothalamus (R
=0.25-0.64). The present study suggests that higher brain regions are coordinated through reflex centers in the brain stem in order to regulate the cardiovascular response to exercise.
The human brain vasculature is of great medical importance: its dysfunction causes disability and death
, and the specialized structure it forms-the blood-brain barrier-impedes the treatment of ...nearly all brain disorders
. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer's disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer's disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer's disease risk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer's disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.
Abstract
It is over 20 years since the inaugural deep inferior epigastric perforator (DIEP) flap breast reconstruction. We review the type of flap utilized and indications in 2,850 microvascular ...breast reconstruction over the subsequent 20 years in the senior author's practice (Robert J. Allen). Data were extracted from a personal logbook of all microsurgical free flap breast reconstructions performed between August 1992 and August 2012. Indication for surgery; mastectomy pattern in primary reconstruction; flap type, whether unilateral or bilateral; recipient vessels; and adjunctive procedures were recorded. The DIEP was the most commonly performed flap (66%), followed by the superior gluteal artery perforator flap (12%), superficial inferior epigastric artery perforator flap (9%), inferior gluteal artery perforator flap (6%), profunda artery perforator flap (3%), and transverse upper gracilis flap (3%). Primary reconstruction accounted for 1,430 flaps (50%), secondary 992 (35%), and tertiary 425 (15%). As simultaneous bilateral reconstructions, 59% flaps were performed. With each flap, there typically ensues a period of enthusiasm which translated into surge in flap numbers. However, each flap has its own nuances and characteristics that influence patient and physician choice. Of note, each newly introduced flap, either buttock or thigh, results in a sharp decline in its predecessor. In this practice, the DIEP flap has remained the first choice in autologous breast reconstruction.
Many decisions involve a trade-off between the quality of an outcome and the time at which that outcome is received. In psychology and behavioral economics, the most widely studied models hypothesize ...that the values of future gains decline as a roughly hyperbolic function of delay from the present. Recently, it has been proposed that this hyperbolic-like decline in value arises from the interaction of two separate neural systems: one specialized to value immediate rewards and the other specialized to value delayed rewards. Here we report behavioral and functional magnetic resonance imaging results that are inconsistent with both the standard behavioral models of discounting and the hypothesis that separate neural systems value immediate and delayed rewards. Behaviorally, we find that human subjects do not necessarily make the impulsive preference reversals predicted by hyperbolic-like discounting. We also find that blood oxygenation level dependent activity in ventral striatum, medial prefrontal, and posterior cingulate cortex does not track whether an immediate reward was present, as proposed by the separate neural systems hypothesis. Activity in these regions was correlated with the subjective value of both immediate and delayed rewards. Rather than encoding only the relative value of one reward compared with another, these values are represented on a more absolute scale. These data support an alternative behavioral-neural model (which we call "ASAP"), in which subjective value declines hyperbolically relative to the soonest currently available reward and a small number of valuation areas serve as a final common pathway through which these subjective values guide choice.
Convergent data from various scientific approaches strongly implicate cerebellar systems in nonmotor functions. The functional anatomy of these systems has been pieced together from disparate ...sources, such as animal studies, lesion studies in humans, and structural and functional imaging studies in humans. To better define this distinct functional anatomy, in the current study we delineate the role of the cerebellum in several nonmotor systems simultaneously and in the same subjects using resting state functional connectivity MRI. Independent component analysis was applied to resting state data from two independent datasets to identify common cerebellar contributions to several previously identified intrinsic connectivity networks (ICNs) involved in executive control, episodic memory/self-reflection, salience detection, and sensorimotor function. We found distinct cerebellar contributions to each of these ICNs. The neocerebellum participates in (1) the right and left executive control networks (especially crus I and II), (2) the salience network (lobule VI), and (3) the default-mode network (lobule IX). Little to no overlap was detected between these cerebellar regions and the sensorimotor cerebellum (lobules V-VI). Clusters were also located in pontine and dentate nuclei, prominent points of convergence for cerebellar input and output, respectively. The results suggest that the most phylogenetically recent part of the cerebellum, particularly crus I and II, make contributions to parallel cortico-cerebellar loops involved in executive control, salience detection, and episodic memory/self-reflection. The largest portions of the neocerebellum take part in the executive control network implicated in higher cognitive functions such as working memory.
Vascular contributions to dementia and Alzheimer's disease are increasingly recognized
. Recent studies have suggested that breakdown of the blood-brain barrier (BBB) is an early biomarker of human ...cognitive dysfunction
, including the early clinical stages of Alzheimer's disease
. The E4 variant of apolipoprotein E (APOE4), the main susceptibility gene for Alzheimer's disease
, leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes
, which maintain BBB integrity
. It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography
. High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ
in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway
in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4-associated cognitive decline independently of Alzheimer's disease pathology, and might be a therapeutic target in APOE4 carriers.
Many important cell types in adult vertebrates have a mesenchymal origin, including fibroblasts and vascular mural cells. Although their biological importance is undisputed, the level of mesenchymal ...cell heterogeneity within and between organs, while appreciated, has not been analyzed in detail. Here, we compare single-cell transcriptional profiles of fibroblasts and vascular mural cells across four murine muscular organs: heart, skeletal muscle, intestine and bladder. We reveal gene expression signatures that demarcate fibroblasts from mural cells and provide molecular signatures for cell subtype identification. We observe striking inter- and intra-organ heterogeneity amongst the fibroblasts, primarily reflecting differences in the expression of extracellular matrix components. Fibroblast subtypes localize to discrete anatomical positions offering novel predictions about physiological function(s) and regulatory signaling circuits. Our data shed new light on the diversity of poorly defined classes of cells and provide a foundation for improved understanding of their roles in physiological and pathological processes.
Cerebrovascular reactivity (CVR) is a measure of vascular response to a vasoactive stimulus, and can be used to assess the health of the brain vasculature. In this current study we used different ...analyses of BOLD fMRI responses to CO2 to provide a number of metrics including ramp and step CVR, speed of response and transfer function analysis (TFA). 51 healthy control volunteers between the ages of 18–85 (26 males) were recruited and scanned at 3T field strength. Atlases reflecting voxel-wise means and standard deviations were compiled to assess possible differences in these metrics between four age cohorts. Testing was carried out using an automated computer-controlled gas blender to induce hypercapnia in a step and ramp paradigm, and monitoring end-tidal partial pressures of CO2 (PETCO2) and O2 (PETO2). No significant differences were found for resting PETCO2 values between cohorts. Ramp CVR decreased significantly with age in white matter frontal regions comprising the ACA-MCA watershed area, a finding that may be indicative of age related changes. Similarly, TFA showed that gain was reduced in the left white matter ACA-MCA watershed area as well as the posterior and anterior cingulate cortex, and superior frontal gyrus in the oldest compared to youngest cohort. These findings, detailing changes in cerebrovascular regulation in the healthy aging brain should prove useful in mapping areas of dysregulated blood flow in individuals with vascular risk factors especially those at risk for developing vascular dementia.
•Gray matter cerebrovascular reactivity metrics are largely stable across ages.•White matter cerebrovascular reactivity metrics are largely stable across ages.•The magnitude of the cingulum and frontal regions are affected in old age.•No significant difference in resting end-tidal pressure of carbon dioxide with aging.
Functional connectomics from resting-state fMRI Smith, Stephen M; Vidaurre, Diego; Beckmann, Christian F ...
Trends in cognitive sciences,
12/2013, Letnik:
17, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Highlights • Spontaneous fluctuations in brain activity reflect functional brain networks. • We review rfMRI for mapping the functional connectome. • We review methods for functional connectomics ...network analysis. • We describe the WU–Minn Human Connectome Project. • We present exciting new analyses using the latest-released HCP data.
PDF
