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![Plasma protein leakage induced by vessel disorders and its relation to perivascular alterations of the brain parenchyma. a This schematic representation shows that plasma proteins occur (1) in the plaque cores of AS plaques, (2) in the vessel wall of lipohyalinotic vessels as well as in the perivascular space and in macrophages within the perivascular space, and (3) in the vessel wall of arteriolosclerotic vessels as well as in accompanying macrophages. CAA, on the other hand, is characterized by the deposition of proteins of the extracellular fluid of the brain, i.e. Ab [15] and apoE [133]. b Impact of plasma protein leakage into the brain. Physiologically, extracellular fluid is drained into the perivascular space and along the vascular](profile/Dietmar-Thal/publication/41429809/figure/fig5/AS:667070488387586@1536053406365/Plasma-protein-leakage-induced-by-vessel-disorders-and-its-relation-to-perivascular.png)
Plasma protein leakage induced by vessel disorders and its relation to perivascular alterations of the brain parenchyma. a This schematic representation shows that plasma proteins occur (1) in the plaque cores of AS plaques, (2) in the vessel wall of lipohyalinotic vessels as well as in the perivascular space and in macrophages within the perivascular space, and (3) in the vessel wall of arteriolosclerotic vessels as well as in accompanying macrophages. CAA, on the other hand, is characterized by the deposition of proteins of the extracellular fluid of the brain, i.e. Ab [15] and apoE [133]. b Impact of plasma protein leakage into the brain. Physiologically, extracellular fluid is drained into the perivascular space and along the vascular
Source publication
Cerebral atherosclerosis (AS), small vessel disease (SVD), and cerebral amyloid angiopathy (CAA) are the most prevalent arterial disorders in the aged brain. Pathogenetically, AS and SVD share similar mechanisms: plasma protein leakage into the vessel wall, accumulation of lipid-containing macrophages, and fibrosis of the vessel wall. CAA, on the o...
Contexts in source publication
Context 1
... itself is subclassified into small vessel arterio- sclerosis/atherosclerosis, arteriolosclerosis, and lipohyalinosis/ fibrinoid necrosis. Despite morphological differences, plasma protein leakage into the vessel wall and/or into the perivascular space are common features of all three sub- forms (Figs. 2, 4a). The hierarchical expansion of SVD, encompassing all of its subforms, throughout the brain, as described in detail in ''Small vessel disease'', also argues in favor of a common disease entity with different presenta- tions in larger and smaller vessels rather than three different vessel ...
Context 2
... AS-and SVD-affected vessels, plasma proteins including apoE leak into the vessel wall and accumulate in the respective lesion [1,18,91,92,139,150] (Figs. 1, 2, 4). Plasma proteins also leak into the perivascular space of vessels affected by SVD indicating an alteration of the pre- capillary segment of the BBB [127,139]. ...
Context 3
... SVD-affected arteries leads to a less effective outward transport of the perivascular fluid due to a cessation of the pulsations [146,147], and (3) the SVD-induced leakage of plasma proteins including apoE into the vessel wall and the perivascular space competes for perivascular drainage with the extracellular fluid of the brain [127,136,137,139] (Fig. 4). Therefore, SVD pre- sumably contributes to the accumulation of Ab in the brain leading to CAA and Alzheimer's disease-related Ab plaque deposition. This hypothesis is supported by the association between SVD, CAA, and Ab plaque deposition [13,129] (Table 2) and by the increase of plasma Ab in patients with SVD [35]. Since SVD and CAA ...
Context 4
... pro- moting alterations of the pre-capillary BBB segment. In the light of all these considerations, it is tempting to speculate that chronic plasma protein leakage into the brain and retention of extracellular fluid due to altered perivascular clearance for the above-mentioned reasons contributes to the development of WMLs and/or lacunar infarcts (Fig. 4b) in addition to chronic hypoxia. Such a mechanism causing alterations of tissue is well-known in liver and lung con- gestion. Here, chronic hypoxia and a decreased venous drainage of extracellular fluid and blood lead to a perive- nous parenchymal necrosis with subsequent fibrosis ...
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Background:
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Citations
... 1,2 HTN negatively impacts on cerebral vasculature promoting atherosclerotic changes in larger brain arteries and arteriolosclerosis in smaller vessels. 3 Changes in vessel walls ultimately lead to reduced cerebral blood flow (CBF) and impaired cerebral autoregulation. [4][5][6] HTN is a risk factor for Alzheimer's disease (AD) and cognitive impairment. ...
INTRODUCTION
We examined whether hypertension (HTN) was associated with Alzheimer's disease‐related biomarkers in cerebrospinal fluid (CSF) and how changes in blood pressure (BP) related to changes in CSF biomarkers over time.
METHODS
A longitudinal observation of cognitively healthy normotensive subjects (n = 134, BP < 140/90, with no antihypertensive medication), controlled HTN (n = 36, BP < 140/90, taking antihypertensive medication), and 35 subjects with uncontrolled HTN (BP ≥ 140/90). The follow‐up range was 0.5to15.6 years.
RESULTS
Total tau (T‐tau) and phospho‐tau181 (P‐tau 181) increased in all but controlled HTN subjects (group×time interaction: p < 0.05 for both), but no significant Aβ42 changes were seen. Significant BP reduction was observed in uncontrolled HTN, and it was related to increase in T‐tau (p = 0.001) and P‐tau 181 (p < 0.001).
DISCUSSION
Longitudinal increases in T‐tau and P‐tau 181 were observed in most subjects; however, only uncontrolled HTN had both markers increase alongside BP reductions. We speculate cumulative vascular injury renders the brain susceptible to relative hypoperfusion with BP reduction.
Highlights
Over the course of the study, participants with uncontrolled HTN at baseline showed greater accumulation of CSF total tau and phospho‐tau181 (P‐tau 181) than subjects with normal BP or with controlled HTN.
In the group with uncontrolled HTN, increases in total tau and P‐tau 181 coincided with reduction in BP.
We believe this highlights the role of HTN in vascular injury and suggests decline in cerebral perfusion resulting in increased biomarker concentrations in CSF.
Medication use was the main factor differentiating controlled from uncontrolled HTN, indicating that earlier treatment was beneficial for preventing accumulations of pathology.
... We only included patients with LAA or SVO stroke, as these stroke subtypes are closely associated with atherosclerosis, making them relevant to our hypothesis. Although SVO is often associated with lipohyalinosis, it also encompasses degenerative alterations in vessel walls, including arteriosclerosis, atherosclerosis, and arteriolosclerosis [33]. Osteogenesis imperfecta, caused by mutations in type 1 collagen genes (COL1A1/COL1A2), is associated with atherosclerosis and vascular fragility caused by collagen abnormalities in the cerebral arterial system [34,35]. ...
Recurrence after stroke is common, and associated with a high mortality rate. Degradation of the elastic tissue in the arterial wall has been shown to aggravate atherosclerosis in blood vessels. Considering that type 1 collagen is present in both bone and vascular smooth muscle cells, we explored whether osteoporotic conditions affect the likelihood of stroke recurrence in postmenopausal women following atherosclerotic ischemic stroke. To determine actual bone mineral density (BMD), the Hounsfield unit values in the frontal skull were evaluated using brain computed tomography (CT) scans taken at admission. A multivariate Cox regression analysis was also performed to examine if osteoporosis could independently predict stroke recurrence in postmenopausal patients with large artery atherosclerosis (LAA) or small vessel occlusion (SVO) stroke. This study included 2130 consecutive patients (both males and females aged 50 and older) with acute LAA or SVO strokes. After adjusting for all covariates, hypothetical osteoporosis was identified as an independent predictor of stroke recurrence in female patients ≥50 years with acute LAA or SVO stroke (hazard ratio, 1.84; 95 % confidence interval, 1.05 to 3.24; p = 0.034). Our findings showed that osteoporosis could potentially affect the recurrence of ischemic stroke in postmenopausal patients with LAA or SVO stroke.
... 84 BBB disruption causes neuroinflammation, glial activation, memory loss, and brain edema. 85,86 Pathological remodeling of the vasculature and microvasculature following atherosclerosis and stroke disrupts blood vessel integrity and results in abnormal and impaired blood supply to the brain, leading to VaD. 87 Several studies have shown that VaD prevalence is significantly associated with cerebrovascular diseases, including stroke and small vessel disease, 23,46,88 which may in turn, cause VaD-associated cognitive impairment. 89 Among the glial cells, astrocytes, which have terminal processes called astrocyte end-feet, surround blood vessels in the brain, thereby contributing to BBB integrity and promoting neurovascular coupling. ...
Vascular dementia (VaD) is the second most common type of dementia and is characterized by memory impairment, blood–brain barrier disruption, neuronal cell loss, glia activation, impaired synaptic plasticity, and cholinergic system abnormalities. To effectively prevent and treat VaD a good understanding of the mechanisms underlying its neuropathology is needed. Brain-derived neurotrophic factor (BDNF) is an important neurotrophic factor with multiple functions in the systemic circulation and the central nervous system and is known to regulate neuronal cell survival, synaptic formation, glia activation, and cognitive decline. Recent studies indicate that when compared with normal subjects, patients with VaD have low serum BDNF levels and that BDNF deficiency in the serum and cerebrospinal fluid is an important indicator of VaD. Here, we review current knowledge on the role of BDNF signaling in the pathology of VaD, such as cerebrovascular dysfunction, synaptic dysfunction, and cholinergic system impairment.
... cases exhibit cerebral amyloid angiopathy (CAA), the deposition of Aβ aggregates at the vessel walls of the brain vasculature. 4,[14][15][16][17][18][19][20][21] CAA is also found in many non-AD older adults, in a proportion correlating with age. Current immunotherapeutic approaches may also increase CAA, inducing amyloid related imaging abnormalities (ARIAs). ...
Background
Most of Alzheimer’s disease (AD) cases present cerebrovascular dysfunction (CVD) and neuroinflammation, at both early and late stages of AD progression. Dysfunctional vasculature and glial cells favor Aβ deposition, inducing brain cell stress, neuroinflammation, impaired clearance/ metabolic waste accumulation, blood‐brain barrier permeability, and ultimately leading to neurodegenerative processes and cognitive impairment. Endothelial cells (ECs) and microglial cells are major players in mediating vascular and glial fitness, and therefore clearance and inflammatory response. Our previous findings in vitro demonstrated that Aβ elicits mitochondrial dysregulation and caspase‐mediated apoptosis in ECs and glial cells. We also showed that FDA‐approved carbonic anhydrase inhibitors (CAIs), acetazolamide (ATZ) and methazolamide (MTZ), employed in non‐AD related conditions, hinder these pathological events.
Method
TgSwDI mice, expressing human Amyloid‐β Precursor Protein, APP, carrying the Swedish, Dutch and Iowa mutations, were employed as AD/CAA (Cerebral Amyloid Angiopathy) model. The model is characterized by fibrillar Aβ burden in the cerebral microvasculature and in the parenchyma, starting at 6 months, as well as abundant gliosis. 8‐month‐old Tg animals were fed 8‐month‐CAI‐diet, following which we harvested the brains for biochemical and immunohistochemical assessments.
Result
CAIs significantly reduced brain amyloidosis, and vascular and microglial Aβ accumulation. In addition, CAIs prevented caspase‐3 activation in ECs and microglia, ameliorating vascular and glial fitness, as we observed less microhemorrhages, reduced microgliosis, and microglial pro‐clearance phenotype. We also unveiled a critical novel druggable target, showing that the mitochondrial isozyme Carbonic Anhydrase (CA)‐VB is specifically upregulated in human cerebral endothelial and microglial cells challenged by Aβ, and most importantly is overexpressed in TgSwDI mouse brains, and in human brains of CAA and AD (with CAA) patients.
Conclusion
CAIs promote vascular health, glial anti‐inflammatory/pro‐healing phenotype and Aβ phagocytosis, which may underlie Aβ deposition reduction. This work paves the way for the application of CAIs in clinical trials for AD and CAA, and uncovers CA‐VB as a mediator of cerebral Aβ toxicity in endothelial and microglial cells.
... Cerebral WMLs are demyelinating changes in the white matter of the brain that are mostly caused by autoimmune diseases, cerebral hypoxia, ischemia, and cerebral perfusion deficits; pathologically, people with cerebral leukomalacia have intracranial small arteriosclerosis, high permeability of the blood-cerebrospinal fluid barrier, interstitial changes, and endothelial damage, all of which can lead to cerebral infarction and an increased risk of hemorrhagic transformation after IVT. 32 Fazekas grading is an imaging-based specific index of the degree of cerebral white matter osteoporosis, and the results of this study found that the incidence of sICH was significantly higher in elderly patients with moderate-to-severe cerebral WMLs than in the general population, in which the incidence was 4%. 14 It is currently believed that the main reason for this is that exogenous rt-PA triggers the cleavage of high relative molecular mass kininogenase by mediating the release of large amounts of bradykinin from fibrinolysin, activated coagulation factor XII, and plasma kininase; bradykinin can be involved in the production of inflammatory mediators and the activation of microglia, which increase vascular permeability and lead to the opening of the blood-brain barrier, thus exacerbating brain injury; moreover, plasma kinin also interferes with collagen-induced platelet activation, increasing the risk of sICH. 33,34 Therefore, it is necessary to pay attention to this group of people. ...
Background and Objective: Elderly people are at high prevalence of atherosclerotic cerebral infarction. Cerebral white matter lesions (WMLs) increase the risk of bleeding after intravenous thrombolysis (IVT) although they may also require the IVT. The aim of this study is to develop a clinical nomogram model for post-IVT symptomatic intracranial hemorrhage (sICH), with the aim to prevent sICH in elderly patients with severe WMLs when IVT is being considered. Methods: This is a large single-center retrospective analysis study of elderly patients with severe WMLs receiving IVT from January 2018 to December 2022. Univariate and multi-factor logistic regression analysis were used to construct nomogram model, and a series of validations were performed on the model. Results: More than 2,000 patients with IVT were screened for inclusion in this study after cranial magnetic resonance imaging evaluation. Out of these, 163 elderly patients had cerebral WMLs, and 25 had sICH. In univariate analysis, history of hypertension (p=0.037), hyperlipidemia (p<0.001), NIHSS score before IVT (p<0.001), low-density lipoprotein levels (p=0.016), cholesterol levels (p=0.020), platelet count (p=0.006), systolic blood pressure (p<0.001), diastolic blood pressure (p<0.001) were significantly associated with sICH. In a multifactorial analysis, the NIHSS score before IVT (OR 42.056 CI 7.308-242.012, p<0.001), and diastolic blood pressure (OR 1.050 CI 1.002-1.100, p=0.040) were found to be significantly associated with sICH after IVT. The four most significant risk factors from logistic regression are subsequently fitted to create a predictive model. The accuracy was verified using calibration curves, decision curves, and clinical impact curves, and the model was considered to have strong stability. Conclusions: The NHISS score before IVT and diastolic blood pressure are independent risk factors for sICH after IVT in elderly patients with severe WMLs. The models are highly accurate and can be applied clinically to provide a reliable predictive basis for IVT in elderly patients with severe WMLs.
... Current research suggests that WMLs are a complex phenomenon influenced by multiple factors such as genetic predisposition, age-related susceptibility, vascular anomalies, infection, and toxic exposure [2]. WMLs are histologically characterized by leukoaraiosis, typically caused by the loss of myelin sheaths and axons, with edema and reactive gliosis [3]. Magnetic resonance imaging (MRI) scans utilizing T2-weighted or fluid-attenuated inversion recovery (FLAIR) sequence reveal WMLs as regions of high signal intensity due to their higher water content. ...
Neuroinflammation is assumed as the critical pathophysiologic mechanism of white matter lesions (WMLs), and infiltrated peripheral monocyte-derived macrophages are implicated in the development of neuroinflammation. This study sought to explore the blood molecules that promote the migration of peripheral monocytes to the sites of WMLs. The serum protein expression profiles of patients and Sprague–Dawley rat models with WMLs were detected by data-independent acquisition (DIA) proteomics technique. Compared with corresponding control groups, we acquired 62 and 41 differentially expressed proteins (DEPs) in the serum of patients and model rats with WMLs respectively. Bioinformatics investigations demonstrated that these DEPs were linked to various Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) terms involved in neuroinflammation. Afterward, we identified thrombin-activatable fibrinolysis inhibitor (TAFI) as a shared and overexpressed protein in clinical and animal serum samples, which was further verified by enzyme-linked immunosorbent assay. Additionally, an upregulation of TAFI was also observed in the white matter of rat models, and the inhibition of TAFI impeded the migration of peripheral monocytes to the area of WMLs. In vitro experiments suggested that TAFI could enhance the migration ability of RAW264.7 cells and increase the expression of Ccr2. Our study demonstrates that neuroinflammatory signals can be detected in the peripheral blood of WMLs patients and model rats. TAFI may serve as a potential protein that promotes the migration of peripheral monocytes to WMLs regions, thereby providing a novel molecular target for further investigation into the interaction between the central and peripheral immune systems.
... With aging and cerebrovascular diseases, the structure of blood vessels can exhibit dramatic remodeling [1,2,4,5]. Specific small vessel pathologic features include arteriolosclerosis, arteriovenous malformations, and downstream changes such as lacunar infarcts, leukoaraiosis, micro-infarcts, and hemorrhagic lesions [4,[6][7][8][9]. However, the histomorphologic features related to cerebrovascular malfunction are more heterogeneous than is widely appreciated, and here we focus on a subtype of vascular pathology about which there is relatively little information published. ...
Cerebrovascular pathologies other than frank infarctions are commonly seen in aged brains. Here, we focus on multi-lumen vascular profiles (MVPs), which are characterized by multiple vessel lumens enclosed in a single vascular channel. Little information exists on the prevalence, risk factors, and co-pathologies of MVPs. Therefore, we used samples and data from the University of Kentucky Alzheimer’s Disease Research Center ( n = 91), the University of Kentucky Pathology Department ( n = 31), and the University of Pittsburgh Pathology Department ( n = 4) to study MVPs. Age at death was correlated with MVP density in the frontal neocortex, Brodmann Area 9 ( r = 0.51; p < 0.0001). Exploratory analyses were performed to evaluate the association between conventional vascular risk factors (e.g., hypertension, diabetes), cardiovascular diseases (e.g., heart attack, arrhythmia), and cerebrovascular disease (e.g., stroke); the only nominal association with MVP density was a self-reported history of brain trauma (Prevalence Ratio = 2.1; 95 CI 1.1–3.9, before correcting for multiple comparisons). No specific associations were detected between neuropathological (e.g., brain arteriolosclerosis) or genetic (e.g., APOE ) variables and MVP density. Using a tissue clearing method called SeeDB, we provide 3-dimensional images of MVPs in brain tissue. We conclude that MVPs are an age-related brain pathology and more work is required to identify their clinical-pathological correlation and associated risk factors.
... C.M. Fisher was the first to note that most lacunes were distal to occlusive lesions of small perforating arteries [39,[62][63][64][65][66]. The vessel occlusive lesions include arteriosclerosis/atherosclerosis, arteriolosclerosis and lipohyalinosis [67,68]. The main vessel lesions are summarized in Table 3. ...
The pathophysiology of lacunar infarction is an evolving and debated field, where relevant information comes from histopathology, old anatomical studies and animal models. Only in the last years, have neuroimaging techniques allowed a sufficient resolution to directly or indirectly assess the dynamic evolution of small vessel occlusion and to formulate hypotheses about the tissue status and the mechanisms of damage. The core–penumbra concept was extensively explored in large vessel occlusions (LVOs) both from the experimental and clinical point of view. Then, the perfusion thresholds on one side and the neuroimaging techniques studying the perfusion of brain tissue were focused and optimized for LVOs. The presence of a perfusion deficit in the territory of a single small perforating artery was negated for years until the recent proposal of the existence of a perfusion defect in a subgroup of lacunar infarcts by using magnetic resonance imaging (MRI). This last finding opens pathophysiological hypotheses and triggers a neurovascular multidisciplinary reasoning about how to image this perfusion deficit in the acute phase in particular. The aim of this review is to summarize the pathophysiological issues and the application of the core–penumbra hypothesis to lacunar stroke.
... Slides were stained with hematoxylin and eosin (H&E), Luxol fast blue-periodic acid Schiff (LFB-PAS), and, to assess vascular pathology, with Verhoeff van Gieson as well as congo red. 29 Additionally, a panel of different immunohistochemistry stains was applied to evaluate anatomy and pathology of the perivascular spaces and the adjacent CNS parenchyma, including CD3, Iba1, PLP, NFL, fibrinogen, laminin a1, collagen IV a1, and aquaporin-4 (AQP-4) (Supplementary Table S1). ...
Background:
Virchow-Robin spaces (VRS) have been associated with neurodegeneration and neuroinflammation. However, it remains uncertain to what degree non-dilated or dilated VRS reflect specific features of neuroinflammatory pathology. Thus, we aimed at investigating the clinical relevance of VRS as imaging biomarker in multiple sclerosis (MS) and to correlate VRS to their histopathologic signature.
Methods:
In a cohort study comprising 142 MS patients and 30 control subjects, we assessed the association of non-dilated and dilated VRS to clinical and magnetic resonance imaging (MRI) outcomes. Findings were corroborated in a validation cohort comprising 63 MS patients. Brain blocks from 6 MS patients and 3 non-MS controls were histopathologically processed to correlate VRS to their tissue substrate.
Findings:
In our actively treated clinical cohort, the count of dilated centrum semiovale VRS was associated with increased T1 and T2 lesion volumes. There was no systematic spatial colocalization of dilated VRS with MS lesions. At tissue level, VRS mostly corresponded to arteries and were not associated with MS pathological hallmarks. Interestingly, in our ex vivo cohort comprising mostly progressive MS patients, dilated VRS in MS were associated with signs of small vessel disease.
Interpretation:
Contrary to prior beliefs, these observations suggest that VRS in MS do not associate with an accumulation of immune cells. But instead, these findings indicate vascular pathology as a driver and/or consequence of neuroinflammatory pathology for this imaging feature.
Funding:
NIH, Swedish Society for Medical Research, Swiss National Science Foundation and University of Zurich.
... cases exhibit cerebral amyloid angiopathy (CAA), the deposition of Aβ aggregates at the vessel walls of the brain vasculature. 4,[14][15][16][17][18][19][20][21] CAA is also found in many non-AD older adults, in a proportion correlating with age. Current immunotherapeutic approaches may also increase CAA, inducing amyloid related imaging abnormalities (ARIAs). ...
Introduction:
Cerebrovascular pathology is an early and causal hallmark of Alzheimer's disease (AD), in need of effective therapies.
Methods:
Based on the success of our previous in vitro studies, we tested for the first time in a model of AD and cerebral amyloid angiopathy (CAA), the carbonic anhydrase inhibitors (CAIs) methazolamide and acetazolamide, Food and Drug Administration-approved against glaucoma and high-altitude sickness.
Results:
Both CAIs reduced cerebral, vascular, and glial amyloid beta (Aβ) accumulation and caspase activation, diminished gliosis, and ameliorated cognition in TgSwDI mice. The CAIs also improved microvascular fitness and induced protective glial pro-clearance pathways, resulting in the reduction of Aβ deposition. Notably, we unveiled that the mitochondrial carbonic anhydrase-VB (CA-VB) is upregulated in TgSwDI brains, CAA and AD+CAA human subjects, and in endothelial cells upon Aβ treatment. Strikingly, CA-VB silencing specifically reduces Aβ-mediated endothelial apoptosis.
Discussion:
This work substantiates the potential application of CAIs in clinical trials for AD and CAA.
