Mesenchymal stem cell-derived extracellular vesicles/exosome: A promising therapeutic strategy for intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is the second largest type of stroke with high mortality and morbidity. The vast majority of survivors suffer from serious neurological defects. Despite the well-established etiology and diagnose, there is still some controversy over the ideal treatment strategy. MSC-based therapy has become an attractive and promising strategy for the treatment of ICH through immune regulation and tissue regeneration. However, accumulating studies have revealed that MSC-based therapeutic effects are mainly attributed to the paracrine properties of MSC, especially small extracellular vesicles/exosome (EVs/exo) which are considered to be the key mediators of the protective efficacy from MSCs. Moreover, some papers reported that MSC-EVs/exo have better therapeutic effects than MSCs. Therefore, EVs/exo has become a new choice for the treatment of ICH stroke in recent years. In this review, we mainly concentrate on the current research progress on the use of MSC-EVs/exo in the treatment of ICH and the existing challenges in their transplation from lab to clinical practice.

rTg-D: A novel transgenic rat model of cerebral amyloid angiopathy Type-2.

Background: Cerebral amyloid angiopathy (CAA) is common disorder of the elderly, a prominent comorbidity of Alzheimer's disease, and causes vascular cognitive impairment and dementia. Previously, we generated a transgenic rat model of capillary CAA type-1 that develops many pathological features of human disease. However, a complementary rat model of larger vessel CAA type-2 disease has been lacking. Methods: A novel transgenic rat model (rTg-D) was generated that produces human familial CAA Dutch E22Q mutant amyloid ß-protein (Aß) in brain and develops larger vessel CAA type-2. Quantitative biochemical and pathological analyses were performed to characterize the progression of CAA and associated pathologies in aging rTg-D rats. Results: rTg-D rats begin to accumulate Aß in brain and develop varying levels of larger vessel CAA type-2, in the absence of capillary CAA type-1, starting around 18 months of age. Larger vessel CAA was mainly composed of the Aß40 peptide and most prominent in surface leptomeningeal/pial vessels and arterioles of the cortex and thalamus. Cerebral microbleeds and small vessel occlusions were present mostly in the thalamic region of affected rTg-D rats. In contrast to capillary CAA type-1 the amyloid deposited within the walls of larger vessels of rTg-D rats did not promote perivascular astrocyte and microglial responses or accumulate the Aß chaperone apolipoprotein E. Conclusion: Although variable in severity, the rTg-D rats specifically develop larger vessel CAA type-2 that reflects many of the pathological features of human disease and provide a new model to investigate the pathogenesis of this condition.

Amyloid ß aggregation induces human brain microvascular endothelial cell death with abnormal actin organization.

Cerebral amyloid angiopathy (CAA) is a disease in which amyloid ß (Aß) is deposited on the walls of blood vessels in the brain, making those walls brittle and causing cerebral hemorrhage. However, the mechanism underlying its onset is not well understood. The aggregation and accumulation of Aß cause the occlusion and fragility of blood vessels due to endothelial cell damage, breakdown of the blood-brain barrier, and replacement with elements constituting the blood vessel wall. In this study, we observed the effect of Aß on human primary brain microvascular endothelial cells (hBMECs) in real-time using quantum dot nanoprobes to elucidate the mechanism of vascular weakening by Aß. It was observed that Aß began to aggregate around hBMECs after the start of incubation and that the cells were covered with aggregates. Aß aggregates firmly anchored the cells on the plate surface, and eventually suppressed cell motility and caused cell death. Furthermore, Aß aggregation induced the organization of abnormal actin, resulting in a significant increase in intracellular actin dots over 10 µm2. These results suggest that the mechanism by which Aß forms a fragile vessel wall is as follows: Aß aggregation around vascular endothelial cells anchors them to the substrate, induces abnormal actin organization, and leads to cell death.

The Relationship between the Static and Dynamic Balance of the Body, the Influence of Eyesight and Muscle Tension in the Cervical Spine in CAA Patients-A Pilot Study.

Cerebral amyloid angiopathy (CAA) is one form of disease of the small vessels of the brain and can cause frequent cerebral hemorrhages as well as other types of stroke. The aim of the study was to analyze the static and dynamic balance of the body and changes in the tension of selected muscles of the cervical spine in patients with CAA after stroke, depending on visual control or its absence, compared to healthy volunteers. Eight stroke patients and eight healthy subjects were examined. The functional Unterberger test and the Biodex SD platform were used to test the dynamic equilibrium, on which the static equilibrium was also assessed. Muscle tension was tested with the Luna EMG device. In static tests, the LC muscle (longus colli) was significantly more active with and without visual control (p = 0.016; p = 0.002), and in dynamic tests, significantly higher results for MOS (p = 0.046) were noted. The comparison of the groups led to the conclusion that the more functional deficits, the more difficult it is to keep balance, also with eye control.

Aberrant waste disposal in neurodegeneration: why improved sleep could be the solution.

Sleep takes up a large percentage of our lives and the full functions of this state are still not understood. However, over the last 10 years a new and important function has emerged as a mediator of brain clearance. Removal of toxic metabolites and proteins from the brain parenchyma generated during waking activity and high levels of synaptic processing is critical to normal brain function and only enabled during deep sleep. Understanding of this process is revealing how impaired sleep contributes an important and likely causative role in the accumulation and aggregation of aberrant proteins such as ß-amyloid and phosphorylated tau, as well as inflammation and neuronal damage. We are also beginning to understand how brain slow-wave activity interacts with vascular function allowing the flow of CSF and interstitial fluid to drain into the body's lymphatic system. New methodology is enabling visualization of this process in both animals and humans and is revealing how these processes break down during ageing and disease. With this understanding we can begin to envisage novel therapeutic approaches to the treatment of neurodegeneration, and how reversing sleep impairment in the correct manner may provide a way to slow these processes and improve brain function.

Hemorrhagic stroke and COVID-19 infection: Coincidence or causality?

Amyloid Protein Precursor gene duplication is a rare cause of early-onset Alzheimer's disease that can be associated with Cerebral Amyloid Angiopathy. This condition predisposes cerebrovascular events, specifically, intracerebral hemorrhagic stroke. This report describes a case of first-time intracerebral hemorrhage in a patient with APP gene duplication during SARS-CoV-2 infection, a typically pro-thrombotic and pro-inflammatory condition, as a possible trigger for this condition.

Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders.

Reactive species play an important role in physiological functions. Overproduction of reactive species, notably reactive oxygen (ROS) and nitrogen (RNS) species along with the failure of balance by the body's antioxidant enzyme systems results in destruction of cellular structures, lipids, proteins, and genetic materials such as DNA and RNA. Moreover, the effects of reactive species on mitochondria and their metabolic processes eventually cause a rise in ROS/RNS levels, leading to oxidation of mitochondrial proteins, lipids, and DNA. Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Multiple sclerosis, and Parkinson's diseases. In addition, oxidative stress causing protein misfold may turn to other NDDs include Creutzfeldt-Jakob disease, Bovine Spongiform Encephalopathy, Kuru, Gerstmann-Straussler-Scheinker syndrome, and Fatal Familial Insomnia. An overview of the oxidative stress and mitochondrial dysfunction-linked NDDs has been summarized in this review.

Longitudinal decrease in blood oxygenation level dependent response in cerebral amyloid angiopathy.

Lower blood oxygenation level dependent (BOLD) signal changes in response to a visual stimulus in functional magnetic resonance imaging (fMRI) have been observed in cross-sectional studies of cerebral amyloid angiopathy (CAA), and are presumed to reflect impaired vascular reactivity. We used fMRI to detect a longitudinal change in BOLD responses to a visual stimulus in CAA, and to determine any correlations between these changes and other established biomarkers of CAA progression. Data were acquired from 22 patients diagnosed with probable CAA (using the Boston Criteria) and 16 healthy controls at baseline and one year. BOLD data were generated from the 200 most active voxels of the primary visual cortex during the fMRI visual stimulus (passively viewing an alternating checkerboard pattern). In general, BOLD amplitudes were lower at one year compared to baseline in patients with CAA (p = 0.01) but were unchanged in controls (p = 0.18). The longitudinal difference in BOLD amplitudes was significantly lower in CAA compared to controls (p < 0.001). White matter hyperintensity (WMH) volumes and number of cerebral microbleeds, both presumed to reflect CAA-mediated vascular injury, increased over time in CAA (p = 0.007 and p = 0.001, respectively). Longitudinal increases in WMH (rs = 0.04, p = 0.86) or cerebral microbleeds (rs = -0.18, p = 0.45) were not associated with the longitudinal decrease in BOLD amplitudes.

Susceptibility-Weighted Magnetic Resonance Imaging in the Evaluation of Dementia.

An 88-year-old woman with a clinical diagnosis of Alzheimer's disease and advanced dementia, was evaluated with standard MRI of the brain as well as Susceptibility Weighted Imaging (SWI) with the MRI. SWI revealed more extensive brain microhemorrhages than standard MRI techniques, allowing the radiologic diagnosis of cerebral amyloid angiopathy. SWI shows promise as a more sensitive diagnostic tool than standard brain MRI for the evaluation of patients with dementia.