Neurovascular Health Research Articles

Electronic cigarette exposure disrupts blood-brain barrier integrity and promotes neuroinflammation

Electronic cigarette (e-cigarette) use has grown substantially since inception, particularly among adolescents and combustible tobacco users. Several cigarette smoke constituents with known neurovascular effect are present in e-cigarette liquids or formed during the vapor generation. The present study establishes inhaled models of cigarette and e-cigarette use with normalized nicotine delivery, then characterizes the impact on blood-brain barrier (BBB) function. Sequencing of microvessel RNA following exposure revealed downregulation of several genes with critical roles in BBB function. Reduced protein expression of Occludin and Glut1 is also observed at the tight junction in all groups following exposure. Pro-inflammatory changes in leukocyte-endothelial cell interaction are also noted, and mice exposed to nicotine-free e-cigarettes have impaired novel object recognition performance. On this basis, it is concluded that long term e-cigarette use may adversely impact neurovascular health. The observed effects are noted to be partly independent of nicotine content and nicotine may even serve to moderate the effects of non-nicotinic components on the blood-brain barrier.

Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects.

Aging-induced structural and functional alterations of the neurovascular unit lead to impairment of neurovascular coupling responses, dysregulation of cerebral blood flow, and increased neuroinflammation, all of which contribute importantly to the pathogenesis of age-related vascular cognitive impairment (VCI). There is increasing evidence showing that a decrease in NAD+ availability with age plays a critical role in age-related neurovascular and cerebromicrovascular dysfunction. Our recent studies demonstrate that restoring cellular NAD+ levels in aged mice rescues neurovascular function, increases cerebral blood flow, and improves performance on cognitive tasks. To determine the effects of restoring cellular NAD+ levels on neurovascular gene expression profiles, 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD+ intermediate, for 2weeks. Transcriptome analysis of preparations enriched for cells of the neurovascular unit was performed by RNA-seq. Neurovascular gene expression signatures in NMN-treated aged mice were compared with those in untreated young and aged control mice. We identified 590 genes differentially expressed in the aged neurovascular unit, 204 of which are restored toward youthful expression levels by NMN treatment. The transcriptional footprint of NMN treatment indicates that increased NAD+ levels promote SIRT1 activation in the neurovascular unit, as demonstrated by analysis of upstream regulators of differentially expressed genes as well as analysis of the expression of known SIRT1-dependent genes. Pathway analysis predicts that neurovascular protective effects of NMN are mediated by the induction of genes involved in mitochondrial rejuvenation, anti-inflammatory, and anti-apoptotic pathways. In conclusion, the recently demonstrated protective effects of NMN treatment on neurovascular function can be attributed to multifaceted sirtuin-mediated anti-aging changes in the neurovascular transcriptome. Our present findings taken together with the results of recent studies using mitochondria-targeted interventions suggest that mitochondrial rejuvenation is a critical mechanism to restore neurovascular health and improve cerebral blood flow in aging.

NIR-II fluorescence microscopic imaging of cortical vasculature in non-human primates.

Vasculature architecture of the brain can provide revealing information about mental and neurological function and disease. Fluorescence imaging in the second near-infrared (NIR-II) regime with less light scattering is a more promising method for detecting cortical vessels than traditional visible and NIR-I modes.Methods: Clinically approved dye indocyanine green (ICG) was used for NIR-II fluorescence imaging. Here, for the first time, we developed two NIR-II fluorescence microscopy systems for brain vasculature imaging in macaque monkeys. The first is a wide-field microscope with high temporal resolution for measuring blood flow velocity and cardiac impulse period, while the second is a high spatial resolution confocal microscope producing three-dimensional maps of the cortical microvascular network. Both were designed with flexibility to image various cortical locations on the head.Results: Here, ICG was proved to have high brightness in NIR-II region and an 8-fold QY increase in serum than in water. We achieved cerebrovascular functional imaging of monkey with high temporal resolution (25 frames/second) with wide-field microscope. The blood flow velocity of capillaries can be precisely calculated and the cardiac impulse period can be monitored as well. In vivo structural imaging of cerebrovasculature was accomplished with both high spatial lateral resolution (~8 µm) and high signal to background ratio (SBR). Vivid 3D reconstructed NIR-II fluorescence confocal microscopic images up to depth of 470 μm were also realized.Conclusion: This work comprises an important advance towards studies of neurovascular coupling, stroke, and other diseases relevant to neurovascular health in humans.

Neurobiology of resilience in depression: immune and vascular insights from human and animal studies.

Major depressive disorder (MDD) is a chronic and recurrent psychiatric condition characterized by depressed mood, social isolation and anhedonia. It will affect 20% of individuals with considerable economic impacts. Unfortunately, 30–50% of depressed individuals are resistant to current antidepressant treatments. MDD is twice as prevalent in women and associated symptoms are different. Depression's main environmental risk factor is chronic stress, and women report higher levels of stress in daily life. However, not every stressed individual becomes depressed, highlighting the need to identify biological determinants of stress vulnerability but also resilience. Based on a reverse translational approach, rodent models of depression were developed to study the mechanisms underlying susceptibility vs resilience. Indeed, a subpopulation of animals can display coping mechanisms and a set of biological alterations leading to stress resilience. The aetiology of MDD is multifactorial and involves several physiological systems. Exacerbation of endocrine and immune responses from both innate and adaptive systems are observed in depressed individuals and mice exhibiting depression‐like behaviours. Increasing attention has been given to neurovascular health since higher prevalence of cardiovascular diseases is found in MDD patients and inflammatory conditions are associated with depression, treatment resistance and relapse. Here, we provide an overview of endocrine, immune and vascular changes associated with stress vulnerability vs. resilience in rodents and when available, in humans. Lack of treatment efficacy suggests that neuron‐centric treatments do not address important causal biological factors and better understanding of stress‐induced adaptations, including sex differences, could contribute to develop novel therapeutic strategies including personalized medicine approaches.

Restoring retinal neurovascular health via substance P

Regulation of vascular permeability plays a major role in the pathophysiology of visually threatening conditions such as retinal vein occlusion and diabetic retinopathy. Principally, several factors such as vascular endothelial growth factor (VEGF), are up-regulated or induced in response to hypoxia thus adversely affecting the blood-retinal barrier (BRB), resulting in retinal edema and neovascularisation. Furthermore, current evidence supports a dysregulation of the inner retinal neural-vascular integrity as a critical factor driving retinal ganglion cell (RGC) death and visual loss. The principal objective of this study was to interrogate whether Substance P (SP), a constitutive neurotransmitter of amacrine and ganglion cells, may protect against N-methyl-d-aspartate (NMDA)-induced excitotoxic apoptosis of ganglion cells and VEGF-induced vessel leakage in the retina. Tight junctional protein expression and a Vascular Permeability Image Assay were used to determine vascular integrity in vitro. The protective effect of SP on RGC was established in ex vivo retinal explants and in vivo murine models. After NMDA administration, a reduction in TUNEL+ cells and a maintained number of Brn-3a+ cells were found, indicating an inhibition of RGC apoptosis mediated by SP. Additionally, SP maintained endothelial tight junctions and decreased VEGF-induced vascular permeability. In conclusion, administration of SP protects against NMDA apoptosis of RGC and VEGF-induced endothelial barrier breakdown.

Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications.

Connexins are ubiquitous channel forming proteins that assemble as plasma membrane hemichannels and as intercellular gap junction channels that directly connect cells. In the heart, gap junction channels electrically connect myocytes and specialized conductive tissues to coordinate the atrial and ventricular contraction/relaxation cycles and pump function. In blood vessels, these channels facilitate long-distance endothelial cell communication, synchronize smooth muscle cell contraction, and support endothelial-smooth muscle cell communication. In the central nervous system they form cellular syncytia and coordinate neural function. Gap junction channels are normally open and hemichannels are normally closed, but pathologic conditions may restrict gap junction communication and promote hemichannel opening, thereby disturbing a delicate cellular communication balance. Until recently, most connexin-targeting agents exhibited little specificity and several off-target effects. Recent work with peptide-based approaches has demonstrated improved specificity and opened avenues for a more rational approach toward independently modulating the function of gap junctions and hemichannels. We here review the role of connexins and their channels in cardiovascular and neurovascular health and disease, focusing on crucial regulatory aspects and identification of potential targets to modify their function. We conclude that peptide-based investigations have raised several new opportunities for interfering with connexins and their channels that may soon allow preservation of gap junction communication, inhibition of hemichannel opening, and mitigation of inflammatory signaling.

Multiparity improves outcomes after cerebral ischemia in female mice despite features of increased metabovascular risk

Females show a varying degree of ischemic sensitivity throughout their lifespan, which is not fully explained by hormonal or genetic factors. Epidemiological data suggest that sex-specific life experiences such as pregnancy increase stroke risk. This work evaluated the role of parity on stroke outcome. Age-matched virgin (i.e., nulliparous) and multiparous mice were subjected to 60 min of reversible middle cerebral artery occlusion and evaluated for infarct volume, behavioral recovery, and inflammation. Using an established mating paradigm, fetal microchimeric cells present in maternal mice were also tracked after parturition and stroke. Parity was associated with sedentary behavior, weight gain, and higher triglyceride and cholesterol levels. The multiparous brain exhibited features of immune suppression, with dampened baseline microglial activity. After acute stroke, multiparous mice had smaller infarcts, less glial activation, and less behavioral impairment in the critical recovery window of 72 h. Behavioral recovery was significantly better in multiparous females compared with nulliparous mice 1 mo after stroke. This recovery was accompanied by an increase in poststroke angiogenesis that was correlated with improved performance on sensorimotor and cognitive tests. Multiparous mice had higher levels of VEGF, both at baseline and after stroke. GFP+ fetal cells were detected in the blood and migrated to areas of tissue injury where they adopted endothelial morphology 30 d after injury. Reproductive experience has profound and complex effects on neurovascular health and disease. Inclusion of female mice with reproductive experience in preclinical studies may better reflect the life-long patterning of ischemic stroke risk in women.

Brain Function Is Linked to LDL Cholesterol in Older Adults with Cardiovascular Risk.

To determine how cardiovascular risk is associated with working memory task performance and task-related suppression of default-mode network (DMN) activity in cognitively intact older adults. A cross-sectional functional magnetic resonance imaging study of older adults with cardiovascular risk factors. Rotman Research Institute, Baycrest Health Sciences. Thirty older adults with cardiovascular risk factors. Participants provided health information and a blood sample, and underwent functional magnetic resonance imaging during a working memory task and during a breath-hold task to assess cerebrovascular reactivity. Higher plasma low-density lipoprotein cholesterol (LDL-C) was associated with poorer working memory task performance (P = 0.008) and reduced task-related DMN suppression (P = 0.005). A composite index of cardiovascular risk, the Framingham General Cardiovascular Risk Profile, showed no associations with task performance or task-related DMN suppression. These findings were independent of white matter burden and cerebrovascular reactivity and thus cannot be accounted for by individual differences in neurovascular health. These findings suggest a deleterious effect of elevated LDL-C on working memory task performance and task-related DMN suppression in older adults with cardiovascular risk. The relations between the Framingham General Cardiovascular Risk Profile, cognitive task performance, and DMN function require further study.

Cerebral blood flow and autoregulation: current measurement techniques and prospects for noninvasive optical methods.

Cerebral blood flow (CBF) and cerebral autoregulation (CA) are critically important to maintain proper brain perfusion and supply the brain with the necessary oxygen and energy substrates. Adequate brain perfusion is required to support normal brain function, to achieve successful aging, and to navigate acute and chronic medical conditions. We review the general principles of CBF measurements and the current techniques to measure CBF based on direct intravascular measurements, nuclear medicine, X-ray imaging, magnetic resonance imaging, ultrasound techniques, thermal diffusion, and optical methods. We also review techniques for arterial blood pressure measurements as well as theoretical and experimental methods for the assessment of CA, including recent approaches based on optical techniques. The assessment of cerebral perfusion in the clinical practice is also presented. The comprehensive description of principles, methods, and clinical requirements of CBF and CA measurements highlights the potentially important role that noninvasive optical methods can play in the assessment of neurovascular health. In fact, optical techniques have the ability to provide a noninvasive, quantitative, and continuous monitor of CBF and autoregulation.

Intracranial arterial four-dimensional flow is associated with metrics of brain health and Alzheimer's disease

IntroductionAlthough cerebrovascular disease has long been known to co-occur with Alzheimer's disease (AD), recent studies suggest an etiologic contribution to AD pathogenesis. We used four dimensional (4D)-flow magnetic resonance imaging (MRI) to evaluate blood flow and pulsatility indices in the circle of Willis. We hypothesized decreased mean blood flow and increased pulsatility, metrics indicative of poor vascular health, would be associated with cerebral atrophy and an AD cerebrospinal fluid (CSF) profile. MethodsA total of 312 patients along the AD continuum (172 middle aged, 60 cognitively healthy older, 44 mild cognitive impairment, and 36 AD) underwent MRI, CSF, and medical examinations. Regression was used to predict CSF biomarkers and atrophy from 4D-flow and analysis of covariance to compare vascular health between groups. ResultsDecreased mean flow in the middle cerebral artery (MCA) and superior portion of the internal carotid artery (sICA) and increased pulsatility in the MCA were associated with greater brain atrophy. Decreased mean flow in the sICA was associated with lower amyloid beta 1–42 (Aβ42) in the CSF, a pathologic biomarker profile associated with AD. Interestingly, although metrics of flow and pulsatility differed markedly across the AD spectrum, there were no significant differences in cardiovascular risk score, mean arterial pressure, and pulse pressure across the three age-matched older cohorts. DiscussionBy measuring intracranial arterial health directly with 4D-flow MRI, these data suggest that intracranial arterial health is compromised in symptomatic AD. Even after accounting for disease stage, cerebral artery health is associated with atrophy and an AD Aβ42 profile, suggesting neurovascular health may contribute to the etiopathogenesis of AD.

Circulating hematopoietic progenitor cell number is associated with prefrontal cortical thickness, white matter integrity and PTSD duration in combat-exposed veterans

Background Circulating hematopoietic progenitor cells (PCs; CD34+ and CD34+/KDR+) facilitate neurogenesis and neovascularization, promoting increased cortical thickness and white matter integrity in animal models. However, it unknown whether low PCs are associated with trauma symptoms or neurovascular health among veterans. Objectives Determine whether lower PCs are associated with: (1) posttraumatic stress disorder (PTSD) diagnosis, duration and symptoms, (2) decreased prefrontal cortical (PFC) thickness, and (3) reduced white matter integrity, indexed by white matter hypointensities (WMH), and tracts relevant to fear processing: the Uncinate Fasciculus (UF) and Inferior Fronto-Occipital Fasciculus (IFOF). Methods 100 male and 8 female combat-exposed veterans reported PTSD symptoms (43 PTSD+) and were studied by 3T MRI, acquiring whole brain T1-weighted images and, for a subsample ( n = 54), diffusion tensor images. PCs were characterized by flow cytometry. Results Higher CD34+/KDR+ counts were related to greater PFC thickness (DM-PFC and DL-PFC), while higher CD34+ counts were related to better IFOF (but not UF) integrity and fewer WMH, controlling for age, gender, smoking, cardiovascular comorbidities and head injury. In PTSD+ subjects, CD34+/KDR+ counts were inversely related to time since the worst trauma, but not PTSD diagnosis or current symptoms. Conclusions PCs are associated with enhanced white matter integrity and PFC thickness, with potential implications for neurovascular plasticity and fear processing. In patients with PTSD, PCs may exhibit accelerated depletion with increasing time post-trauma.

Inflammatory Mediators May Have Divergent Roles in Cancer and in Alzheimer's Disease

To the Editor: The April 2010 issue of Clinical Pharmacology & Therapeutics focuses on the role of inflammation in the pathogenesis of cancer, obesity, and cardiovascular disease. However, another important disease with an inflammatory component, Alzheimer’s disease (AD), receives only limited attention.1 Epidemiologic studies indicate an inverse association between the incidence of AD and that of cancer;2 on the other hand, there is a direct association between the incidence of both diabetes and cardiovascular disease and that of AD.3 The contribution of immune processes to the pathogenesis of these diseases is now becoming more fully appreciated. For instance, the progression of AD has been correlated with immune processes that promote or inhibit disease progression involving the innate immune system through alterations in the clearance of amyloid by the complement protein C1q, elevation of levels of inflammatory cytokines that worsen amyloid deposition, activation of amyloid protein processing,4 and alteration of the receptor for advanced glycolytic end products. Our current understanding of the importance of the innate and adaptive immune system in cancer immunosurveillance can help us to conceptualize a similar paradigm for other diseases, such as AD. The cancer immunosurveillance hypothesis proposes that the differences between no disease, a smoldering disease state, and progression are dependent on the shift in balance between a tolerogenic protumor immune state and an active antitumor response. Similarly, the pathogenesis of AD is likely to be influenced by a variety of intrinsic and extrinsic factors, including the age of the immune system, neurovascular health, tissue damage, and infection. The same proinflammatory responses that contribute to an antitumorigenic response in neoplastic disease may promote tissue destruction and exacerbation of AD. Conversely, the tolerogenic protumor immune responses may be beneficial to AD patients. This model may explain the observed inverse association between the two diseases. The decreased or delayed occurrence of cancer in AD patients might be due to the nature of the immune response in these individuals, favoring AD progression while retarding cancer development. In effect, the production of mediators as by-products of the inflammatory process activated during the amyloid cascade in AD patients may be “good” for inhibiting cancer development but “bad” because they may promote AD.5 An improved understanding of the dynamics of the immune environment in AD and cancer is likely to lead to novel therapeutic approaches that shift the immune balance to a more favorable clinical outcome.

Should We Distinguish Between Periventricular and Deep White Matter Hyperintensities?

To the Editor: The recent article by DeCarli et al1 addresses a somewhat neglected aspect of white matter hyperintensities (WMH), the significance of their anatomical location. The authors argue that the commonly accepted categorization into deep (DWMH) and periventricular (PVWMH) WMH is arbitrary, because the 2 are very highly correlated, and a spatial analysis does not reveal distinct populations. We think that this conclusion is premature, because the categorization depends on a number of factors. The first limitation of their analysis is that they examined individuals in their 70s who presented to a specialty clinic, suggesting that the white matter lesions in their sample were at an advanced stage. If an analogy is drawn from cerebral atrophy in dementia, regional differences in atrophy that are present in the different subtypes of dementia become less prominent in the later stages. In our study of WMH in middle age (60 to 64 years), the correlation of DWMH and PVWMH was much lower ( r =0.621; …