Untersuchung des Zusammenhangs von hypertensiver Arteriopathie und zerebraler Amyloidangiopathie im Modell der spontan hypertensiven stroke-prone Ratte

Ziel der vorliegenden Arbeit war die Etablierung der 2-Photonen-Mikroskopie (2PM) am Tiermodell der spontan hypertensiven stroke-prone Ratte (SHRSP), um die Pathologien der hypertensiven Arteriopathie (HA) intravital sowie postmortal darstellen zu können. Zusätzlich sollte getestet werden, ob der durch die HA induzierte Gefäßschaden ebenfalls die Entwicklung einer zerebralen Amyloidangiopathie (CAA) begünstigt. Für die Studie erfolgte die 2PM zur Darstellung der kortikalen Arteriolen mit Hilfe des fluoreszenzmarkierten Farbstoffes Dextran, die zerebrale Blutflussmessung sowie die intravitale Bildgebung mit dem Fluoreszenz-Farbstoff Methoxy-X04 zur Darstellung vaskulärer Amyloid-Ablagerungen. Postmortal erfolgte die histologische und immunhistochemische Untersuchung des Operationsgebietes auf das Vorhandensein einer HA und CAA. Es konnte gezeigt werden, dass die HA in der SRHSP initial durch einen Gefäßwandschaden (Stadium 1A) sowie eine Blutfluss-Reduktion (Stadium 1B) charakterisiert ist und in der Ausbildung nicht-okkludierender (Stadium 2) und okkludierender Thromben (Stadium 3) resultiert. Wistar-Kontrolltiere zeigten intravital ebenfalls einen Gefäßwandschaden, waren jedoch nicht durch die Ausbildung der späteren HA-Stadien charakterisiert. Zusätzlich wiesen etwa die Hälfte aller SHRSP vaskuläre Amyloid-Ablagerungen in Form einer CAA auf, die sich vornehmlich in Gefäßen mit unvollständigen bzw. vollständigen Gefäßverschlüssen (Stadium 2 oder 3) darstellten. Die Daten deuten somit darauf hin, dass eine fortgeschrittene HA bei der CAA-Entwicklung eine entscheidende Rolle spielt und beide Krankheitsbilder eng miteinander verbunden sind

The association between hypertensive arteriopathy and cerebral amyloid angiopathy in spontaneously hypertensive stroke-prone rats

We aimed to test the hypothesis that in spontaneously hypertensive stroke-prone rats (SHRSP), non-amyloid cerebral small vessel disease/hypertensive arteriopathy (HA) results in vessel wall injury that may promote cerebral amyloid angiopathy (CAA). Our study comprised 21 male SHRSP (age 17–44 weeks) and 10 age- and sex-matched Wistar control rats, that underwent two-photon (2PM) imaging of the arterioles in the parietal cortex using Methoxy-X04, Dextran and cerebral blood flow (CBF) measurements. Our data suggest that HA in SHRSP progresses in a temporal and age-dependent manner, starting from small vessel wall damage (stage 1A), proceeding to CBF reduction (stage 1B), non-occlusive (stage 2), and finally, occlusive thrombi (stage 3). Wistar animals also demonstrated small vessel wall damage, but were free of any of the later HA stages. Nearly half of all SHRSP additionally displayed vascular Methoxy-X04 positivity indicative of cortical CAA. Vascular β-amyloid deposits were found in small vessels characterized by thrombotic occlusions (stage 2 or 3). Post-mortem analysis of the rat brains confirmed the findings derived from intravital 2PM microscopy. Our data thus overall suggest that advanced HA may play a role in CAA development with the two small vessel disease entities might be related to the same pathological spectrum of the aging brain

Retinal Vascular Pathology in a Rat Model of Cerebral Small Vessel Disease

Introduction: The initial disease stages of hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA), the two main forms of sporadic human cerebral small vessel diseases (CSVD), are too subtle to be detectable on clinical routine imaging. Small vessel disease (SVD) is a systemic condition, affecting not only the brain, but also other organs. The retina appears as an ideal marker for the early detection of incipient CSVD. We therefore investigated the retinal microvasculature of the spontaneously hypertensive stroke-prone rat (SHRSP), an animal model of sporadic CSVD. Materials and Methods: The brains and retinas of 26 male SHRSP (18-44 weeks) were examined histologically and immunohistochemically for the presence of HA phenomena (erythrocyte thrombi, small perivascular bleeds) and amyloid angiopathy (AA). Results: CAA and AA in the retina showed a significant correlation with age (CAA: rho = 0.55, p = 0.005; AA: rho = 0.89, p < 0.001). The number of erythrocyte thrombi in the brain correlated with the severity of retinal erythrocyte thrombi (rho = 0.46, p = 0.023), while the occurrence of CAA correlated with the appearance of AA in the retina (rho = 0.51, p = 0.012). Retinal SVD markers predicted CSVD markers with good sensitivity. Conclusions: These results indicate that SVD also occurs in the retinal microvasculature of SHRSP and the prediction of cerebral erythrocyte thrombi and CAA might be possible using retinal biomarkers. This underlines the important role of the investigation of the retina in the early diagnosis of CSVD.

The association between hypertensive arteriopathy and cerebral amyloid angiopathy in spontaneously hypertensive stroke-prone rats

We aimed to test the hypothesis that in spontaneously hypertensive stroke-prone rats (SHRSP), non-amyloid cerebral small vessel disease/hypertensive arteriopathy (HA) results in vessel wall injury that may promote cerebral amyloid angiopathy (CAA). Our study comprised 21 male SHRSP (age 17–44 weeks) and 10 age- and sex-matched Wistar control rats, that underwent two-photon (2PM) imaging of the arterioles in the parietal cortex using Methoxy-X04, Dextran and cerebral blood flow (CBF) measurements. Our data suggest that HA in SHRSP progresses in a temporal and age-dependent manner, starting from small vessel wall damage (stage 1A), proceeding to CBF reduction (stage 1B), non-occlusive (stage 2), and finally, occlusive thrombi (stage 3). Wistar animals also demonstrated small vessel wall damage, but were free of any of the later HA stages. Nearly half of all SHRSP additionally displayed vascular Methoxy-X04 positivity indicative of cortical CAA. Vascular β-amyloid deposits were found in small vessels characterized by thrombotic occlusions (stage 2 or 3). Post-mortem analysis of the rat brains confirmed the findings derived from intravital 2PM microscopy. Our data thus overall suggest that advanced HA may play a role in CAA development with the two small vessel disease entities might be related to the same pathological spectrum of the aging brain.</p

Methods of applied mathematics with a software overview

This textbook, now in its second edition, provides students with a firm grasp of the fundamental notions and techniques of applied mathematics as well as the software skills to implement them. The text emphasizes the computational aspects of problem solving as well as the limitations and implicit assumptions inherent in the formal methods. Readers are also given a sense of the wide variety of problems in which the presented techniques are useful. Broadly organized around the theme of applied Fourier analysis, the treatment covers classical applications in partial differential equations and boundary value problems, and a substantial number of topics associated with Laplace, Fourier, and discrete transform theories. Some advanced topics are explored in the final chapters such as short-time Fourier analysis and geometrically based transforms applicable to boundary value problems. The topics covered are useful in a variety of applied fields such as continuum mechanics, mathematical physics, control theory, and signal processing. Replete with helpful examples, illustrations, and exercises of varying difficulty, this text can be used for a one- or two-semester course and is ideal for students in pure and applied mathematics, physics, and engineering. Key features of the software overview: Now relies solely on the free software tools Octave, Maxima, and Python. Appendix introduces all of these tools at a level suitable to those with some programming experience Provides references to sources of further learning. Code snippets incorporated throughout the text. All graphics and illustrations generated using these tools. Praise for the first edition: “The author mixed in a remarkable way theoretical results and applications illustrating the results. Flexibility of presentation (increasing and decreasing level of rigor, accessibility) is a key feature...The book contains extensive examples, presented in an intuitive way with high quality figures (some of them quite spectacular)…” – Mathematica “...Davis's book has many novel features being quite different from most other textbooks on applied mathematics.... Mainly it has a clear and consistent exposition with a strong focus on mathematical fundamentals and useful techniques. It has numerous extensive examples, illustrations, comments, and a very modern graphical presentation of results. “…The book has style. Every theorem and mathematical result has a wonderful appealing comment.” – Studies in Informatics and Control

Hypercholesterolemia induced cerebral small vessel disease

<div><p>Background</p><p>While hypercholesterolemia plays a causative role for the development of ischemic stroke in large vessels, its significance for cerebral small vessel disease (CSVD) remains unclear. We thus aimed to understand the detailed relationship between hypercholesterolemia and CSVD using the well described <i>Ldlr</i>^<i>-/-</i> mouse model.</p><p>Methods</p><p>We used <i>Ldlr</i>^<i>-/-</i> mice (n = 16) and wild-type (WT) mice (n = 15) at the age of 6 and 12 months. <i>Ldlr</i>^<i>-/-</i> mice develop high plasma cholesterol levels following a high fat diet. We analyzed cerebral capillaries and arterioles for intravascular erythrocyte accumulations, thrombotic vessel occlusions, blood-brain barrier (BBB) dysfunction and microbleeds.</p><p>Results</p><p>We found a significant increase in the number of erythrocyte stases in 6 months old <i>Ldlr</i>^<i>-/-</i> mice compared to all other groups (<i>P</i> < 0.05). <i>Ldlr</i>^<i>-/-</i> animals aged 12 months showed the highest number of thrombotic occlusions while in WT animals hardly any occlusions could be observed (<i>P</i> < 0.001). Compared to WT mice, <i>Ldlr</i>^<i>-/-</i> mice did not display significant gray matter BBB breakdown. Microhemorrhages were observed in one <i>Ldlr</i>^<i>-/-</i> mouse that was 6 months old. Results did not differ when considering subcortical and cortical regions.</p><p>Conclusions</p><p>In <i>Ldlr</i>^<i>-/-</i> mice, hypercholesterolemia is related to a thrombotic CSVD phenotype, which is different from hypertension-related CSVD that associates with a hemorrhagic CSVD phenotype. Our data demonstrate a relationship between hypercholesterolemia and the development of CSVD. <i>Ldlr</i>^<i>-/-</i> mice appear to be an adequate animal model for research into CSVD.</p></div