The shared role of amyloid-β (Aβ) deposition in cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD) is arguably the clearest instance of crosstalk between neurodegenerative and ...cerebrovascular processes. The pathogenic pathways of CAA and AD intersect at the levels of Aβ generation, its circulation within the interstitial fluid and perivascular drainage pathways and its brain clearance, but diverge in their mechanisms of brain injury and disease presentation. Here, we review the evidence for and the pathogenic implications of interactions between CAA and AD. Both pathologies seem to be driven by impaired Aβ clearance, creating conditions for a self-reinforcing cycle of increased vascular Aβ, reduced perivascular clearance and further CAA and AD progression. Despite the close relationship between vascular and plaque Aβ deposition, several factors favour one or the other, such as the carboxy-terminal site of the peptide and specific co-deposited proteins. Amyloid-related imaging abnormalities that have been seen in trials of anti-Aβ immunotherapy are another probable intersection between CAA and AD, representing overload of perivascular clearance pathways and the effects of removing Aβ from CAA-positive vessels. The intersections between CAA and AD point to a crucial role for improving vascular function in the treatment of both diseases and indicate the next steps necessary for identifying therapies.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Post-Stroke Cognitive Impairment and Dementia Rost, Natalia S; Brodtmann, Amy; Pase, Matthew P ...
Circulation research,
2022-Apr-15, 2022-04-15, 20220415, Volume:
130, Issue:
8
Journal Article
Peer reviewed
Poststroke cognitive impairment and dementia (PSCID) is a major source of morbidity and mortality after stroke worldwide. PSCID occurs as a consequence of ischemic stroke, intracerebral hemorrhage, ...or subarachnoid hemorrhage. Cognitive impairment and dementia manifesting after a clinical stroke is categorized as vascular even in people with comorbid neurodegenerative pathology, which is common in elderly individuals and can contribute to the clinical expression of PSCID. Manifestations of cerebral small vessel disease, such as covert brain infarcts, white matter lesions, microbleeds, and cortical microinfarcts, are also common in patients with stroke and likewise contribute to cognitive outcomes. Although studies of PSCID historically varied in the approach to timing and methods of diagnosis, most of them demonstrate that older age, lower educational status, socioeconomic disparities, premorbid cognitive or functional decline, life-course exposure to vascular risk factors, and a history of prior stroke increase risk of PSCID. Stroke characteristics, in particular stroke severity, lesion volume, lesion location, multiplicity and recurrence, also influence PSCID risk. Understanding the complex interaction between an acute stroke event and preexisting brain pathology remains a priority and will be critical for developing strategies for personalized prediction, prevention, targeted interventions, and rehabilitation. Current challenges in the field relate to a lack of harmonization of definition and classification of PSCID, timing of diagnosis, approaches to neurocognitive assessment, and duration of follow-up after stroke. However, evolving knowledge on pathophysiology, neuroimaging, and biomarkers offers potential for clinical applications and may inform clinical trials. Preventing stroke and PSCID remains a cornerstone of any strategy to achieve optimal brain health. We summarize recent developments in the field and discuss future directions closing with a call for action to systematically include cognitive outcome assessment into any clinical studies of poststroke outcome.
Air pollution and climate change have a significant impact on human health and well‐being and contribute to the onset and aggravation of allergic rhinitis and asthma among other chronic respiratory ...diseases. In Westernized countries, households have experienced a process of increasing insulation and individuals tend to spend most of their time indoors. These sequelae implicate a high exposure to indoor allergens (house dust mites, pets, molds, etc), tobacco smoke, and other pollutants, which have an impact on respiratory health. Outdoor air pollution derived from traffic and other human activities not only has a direct negative effect on human health but also enhances the allergenicity of some plants and contributes to global warming. Climate change modifies the availability and distribution of plant‐ and fungal‐derived allergens and increases the frequency of extreme climate events. This review summarizes the effects of indoor air pollution, outdoor air pollution, and subsequent climate change on asthma and allergic rhinitis in children and adults and addresses the policy adjustments and lifestyle changes required to mitigate their deleterious effects.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Paravascular drainage of solutes, including β-amyloid (Aβ), appears to be an important process in brain health and diseases such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). ...However, the major driving force for clearance remains largely unknown. Here we used in vivo two-photon microscopy in awake head-fixed mice to assess the role of spontaneous vasomotion in paravascular clearance. Vasomotion correlated with paravascular clearance of fluorescent dextran from the interstitial fluid. Increasing the amplitude of vasomotion by means of visually evoked vascular responses resulted in increased clearance rates in the visual cortex of awake mice. Evoked vascular reactivity was impaired in mice with CAA, which corresponded to slower clearance rates. Our findings suggest that low-frequency arteriolar oscillations drive drainage of solutes. Targeting naturally occurring vasomotion in patients with CAA or AD may be a promising early therapeutic option for prevention of Aβ accumulation in the brain.
•Spontaneous low-frequency oscillations can be observed in arterioles in awake mice•Vasomotion drives paravascular clearance of solutes from the brain•Paravascular clearance is impaired in the context of cerebral amyloid angiopathy
van Veluw et al. demonstrate that vasomotion is a major driving force for paravascular clearance of solutes from the brain. Loss of vascular smooth muscle cells and reduced vasomotion in the context of amyloid deposition is associated with impaired clearance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
During cardiogenesis, most myocytes arise from cardiac progenitors expressing the transcription factors Isl1 and Nkx2‐5. Here, we show that a direct repression of Isl1 by Nkx2‐5 is necessary for ...proper development of the ventricular myocardial lineage. Overexpression of Nkx2‐5 in mouse embryonic stem cells (ESCs) delayed specification of cardiac progenitors and inhibited expression of Isl1 and its downstream targets in Isl1+ precursors. Embryos deficient for Nkx2‐5 in the Isl1+ lineage failed to downregulate Isl1 protein in cardiomyocytes of the heart tube. We demonstrated that Nkx2‐5 directly binds to an Isl1 enhancer and represses Isl1 transcriptional activity. Furthermore, we showed that overexpression of Isl1 does not prevent cardiac differentiation of ESCs and in Xenopus laevis embryos. Instead, it leads to enhanced specification of cardiac progenitors, earlier cardiac differentiation, and increased cardiomyocyte number. Functional and molecular characterization of Isl1‐overexpressing cardiomyocytes revealed higher beating frequencies in both ESC‐derived contracting areas and Xenopus Isl1‐gain‐of‐function hearts, which associated with upregulation of nodal‐specific genes and downregulation of transcripts of working myocardium. Immunocytochemistry of cardiomyocyte lineage‐specific markers demonstrated a reduction of ventricular cells and an increase of cells expressing the pacemaker channel Hcn4. Finally, optical action potential imaging of single cardiomyocytes combined with pharmacological approaches proved that Isl1 overexpression in ESCs resulted in normally electrophysiologically functional cells, highly enriched in the nodal subtype at the expense of the ventricular lineage. Our findings provide an Isl1/Nkx2‐5‐mediated mechanism that coordinately regulates the specification of cardiac progenitors toward the different myocardial lineages and ensures proper acquisition of myocyte subtype identity. Stem Cells 2015;33:1113–1129
Objective
Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid β (Aβ) in the walls of cortical vessels and the accrual of microbleeds and microinfarcts over time. The ...relationship between CAA severity and microbleeds and microinfarcts as well as the sequence of events that lead to lesion formation remain poorly understood.
Methods
We scanned intact formalin‐fixed hemispheres of 12 CAA cases with magnetic resonance imaging (MRI), followed by histopathological examination in predefined areas and serial sectioning in targeted areas with multiple lesions.
Results
In total, 1,168 cortical microbleeds and 472 cortical microinfarcts were observed on ex vivo MRI. Increasing CAA severity at the whole‐brain or regional level was not associated with the number of microbleeds or microinfarcts. However, locally, the density of Aβ‐positive cortical vessels was lower surrounding a microbleed compared to a simulated control lesion, and higher surrounding microinfarcts. Serial sectioning revealed that for (n = 28) microbleeds, both Aβ (4%) and smooth muscle cells (4%) were almost never present in the vessel wall at the site of bleeding, but Aβ was frequently observed upstream or downstream (71%), as was extensive fibrin(ogen) buildup (87%). In contrast, for (n = 22) microinfarcts, vascular Aβ was almost always observed at the core of the lesion (91%, p < 0.001) as well as upstream or downstream (82%), but few vessels associated with microinfarcts had intact smooth muscle cells (9%).
Interpretation
These observations provide a model for how a single neuropathologic process such as CAA may result in hemorrhagic or ischemic brain lesions potentially through 2 different mechanistic pathways. ANN NEUROL 2019;86:279–292
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
According to the hygiene hypothesis, the increasing incidence of autoimmune diseases in western countries may be explained by changes in early microbial exposure, leading to altered immune ...maturation. We followed gut microbiome development from birth until age three in 222 infants in Northern Europe, where early-onset autoimmune diseases are common in Finland and Estonia but are less prevalent in Russia. We found that Bacteroides species are lowly abundant in Russians but dominate in Finnish and Estonian infants. Therefore, their lipopolysaccharide (LPS) exposures arose primarily from Bacteroides rather than from Escherichia coli, which is a potent innate immune activator. We show that Bacteroides LPS is structurally distinct from E. coli LPS and inhibits innate immune signaling and endotoxin tolerance; furthermore, unlike LPS from E. coli, B. dorei LPS does not decrease incidence of autoimmune diabetes in non-obese diabetic mice. Early colonization by immunologically silencing microbiota may thus preclude aspects of immune education.
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•Finnish and Estonian infants have a distinct early gut microbiome compared to Russians•B. dorei and other Bacteroides species are highly abundant in Finland and Estonia•B. dorei LPS inhibits the immunostimulatory activity of E. coli LPS•LPS from B. dorei does not protect NOD mice from type 1 diabetes
Bacteroides species in the microbiota of children from countries with high susceptibility to autoimmunity produce a type of lipopolysaccharide (LPS) with immunoinhibitory properties. These properties may preclude early immune education and contribute to the development of type 1 diabetes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The role of innate immune cells in allergen immunotherapy that confers immune tolerance to the sensitizing allergen is unclear. Here, we report a role of interleukin-10-producing type 2 innate ...lymphoid cells (IL-10+ ILC2s) in modulating grass-pollen allergy. We demonstrate that KLRG1+ but not KLRG1– ILC2 produced IL-10 upon activation with IL-33 and retinoic acid. These cells attenuated Th responses and maintained epithelial cell integrity. IL-10+ KLRG1+ ILC2s were lower in patients with grass-pollen allergy when compared to healthy subjects. In a prospective, double-blind, placebo-controlled trial, we demonstrated that the competence of ILC2 to produce IL-10 was restored in patients who received grass-pollen sublingual immunotherapy. The underpinning mechanisms were associated with the modification of retinol metabolic pathway, cytokine-cytokine receptor interaction, and JAK-STAT signaling pathways in the ILCs. Altogether, our findings underscore the contribution of IL-10+ ILC2s in the disease-modifying effect by allergen immunotherapy.
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•A thorough characterization of IL-10-producing type 2 innate lymphoid cell (ILC2s)•IL-10-producing ILC2s restore epithelial cell integrity and suppress Th2 responses•Symptom severity inversely correlates with IL-10-producing ILC2s after immunotherapy•IL-10-producing ILC2s play a critical role in tolerance induction to aeroallergens
Underpinning mechanisms of immune tolerance following allergen immunotherapy is not well understood. Golebski et al. characterized IL-10-producing type 2 innate lymphoid cell and report that these cells with regulatory properties are induced following immunotherapy suggesting that they play an essential role in immune tolerance to aeroallergens in upper respiratory disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The perception of self and others is a key aspect of social cognition. In order to investigate the neurobiological basis of this distinction we reviewed two classes of task that study self-awareness ...and awareness of others (theory of mind, ToM). A reliable task to measure self-awareness is the recognition of one’s own face in contrast to the recognition of others’ faces. False-belief tasks are widely used to identify neural correlates of ToM as a measure of awareness of others. We performed an activation likelihood estimation meta-analysis, using the fMRI literature on self-face recognition and false-belief tasks. The brain areas involved in performing false-belief tasks were the medial prefrontal cortex (MPFC), bilateral temporo-parietal junction, precuneus, and the bilateral middle temporal gyrus. Distinct self-face recognition regions were the right superior temporal gyrus, the right parahippocampal gyrus, the right inferior frontal gyrus/anterior cingulate cortex, and the left inferior parietal lobe. Overlapping brain areas were the superior temporal gyrus, and the more ventral parts of the MPFC. We confirmed that self-recognition in contrast to recognition of others’ faces, and awareness of others involves a network that consists of separate, distinct neural pathways, but also includes overlapping regions of higher order prefrontal cortex where these processes may be combined. Insights derived from the neurobiology of disorders such as autism and schizophrenia are consistent with this notion.
Sporadic cerebral small vessel disease (SVD) is a major contributor to vascular cognitive impairment and dementia in the aging human brain. On neuropathology, sporadic SVD is characterized by ...abnormalities to the small vessels of the brain predominantly in the form of cerebral amyloid angiopathy and arteriolosclerosis. These pathologies frequently coexist with Alzheimer disease changes, such as plaques and tangles, in a single brain. Conversely, during life, magnetic resonance imaging (MRI) only captures the larger manifestations of SVD in the form of parenchymal brain abnormalities. There appears to be a major knowledge gap regarding the underlying neuropathology of individual MRI-detectable SVD abnormalities. Ex vivo MRI in postmortem human brain tissue is a powerful tool to bridge this gap. This review summarizes current insights into the histopathologic correlations of MRI manifestations of SVD, their underlying cause, presumed pathophysiology, and associated secondary tissue injury. Moreover, we discuss the advantages and limitations of ex vivo MRI-guided histopathologic investigations and make recommendations for future studies.
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