Quantitative analysis of the capillary network of aged APPswe/PS1dE9 transgenic mice

Yin

National Science Review

et al. 2019

Accumulating evidence indicates the critical importance of cerebrovascular dysfunction in the pathogenesis of Alzheimer's disease (AD). However, systematic comparative studies on the precise brain vasculature of wild-type and AD model mice are still rare. Using an image-optimization method for analysing Micro-Optical Sectioning Tomography (MOST) data, we generated cross-scale whole-brain 3D atlases that cover the entire vascular system from large vessels down to smallest capillaries at submicron resolution, for both wild-type mice and a transgenic (APP/PS1) mouse model of AD. In addition to distinct vascular patterns in different brain regions, we found that the main vessels of the molecular layer of the hippocampal dentate gyrus (DG-ml) undergo abrupt changes in both diameter and branch angle, spreading a unique comb-like pattern of capillaries. By using a quantitative analysis workflow, we identified in the hippocampus of AD mice an overall reduction of the mean vascular diameter, volume fraction and branch angle, with most significant impairment in the DG-ml. In addition, virtual endoscopy revealed irregular morphological features in the vessel lumen of the AD mice, potentially contributing to the impairment of blood flow. Our results demonstrate the capability of high-resolution cross-scale evaluation of brain vasculature and underscore the importance of studying hippocampal microcirculation for understanding AD pathogenesis.

Section: Discussionmentioning

confidence: 99%

High-resolution mapping of brain vasculature and its impairment in the hippocampus of Alzheimer's disease mice

Yin

National Science Review

et al. 2019

“…As pointed out in previous publications (Dorph-Petersen et al, 2001 ; Nikolajsen et al, 2015 ), tissue shrinkage is a major problem when analyzing length parameters in conventional light microscopic preparations. This because the absolute or true length of linear features, unlike object number, is sensitive to the volumetric distortions in the tissue The increasing use of in vivo 3D imaging of biological tissue can be expected to eliminate these problems.…”

Section: Two Ways To Make Estimates Of Total Length L mentioning

confidence: 90%

“…This because the absolute or true length of linear features, unlike object number, is sensitive to the volumetric distortions in the tissue The increasing use of in vivo 3D imaging of biological tissue can be expected to eliminate these problems. For example, a comparison of estimates of length density, using space ball probes in neocortical tissue of DBA mice that had been fixed for light microscopy, 2,857 mm/mm 3 , (Nikolajsen et al, 2015 ) and in similar mice of the same age, viewed in vivo with 2 photon microscopy, (720 mm/mm 3) (Gutiérrez-Jiménez et al, 2018 ) indicate that the length density estimates in the histological material were about four times those for the in vivo estimates. This comparison, although limited to only part of the cortex in the in vivo material, indicates that the length density of capillaries in light microscopic preparations, increases roughly in proportion to the reduction in volume of the processed tissue.…”

Section: Two Ways To Make Estimates Of Total Length L mentioning

confidence: 99%

“…Examples using space ball probes include; the length of dopaminergic axons, which can be related to the dopaminergic innervation and function of the striatum (Li et al, 2016 ); the length of serotoninergic (Liu et al, 2011 ) and cholinergic axons in cerebral cortex which can be related to cortical function (Nikolajsen et al, 2011 ) and the length of astrocyte processes, which can be related to immune-reactivity (McNeal et al, 2016 ). These parameters can be used to evaluate brain hemodynamics (Kubíková et al, 2018 ), tissue oxygenation (Nikolajsen et al, 2015 ), and tissue repair (Lee et al, 2005 ; McConnell et al, 2016 ) and ultimately used to develop therapeutic approaches to brain disorders. Structural parameters of potential interest and for which quantitative studies of length have yet to be carried out include microtubules, involved in intracellular transport, and neuropil threads, an expression of Alzheimer's disease.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Space Balls Revisited: Stereological Estimates of Length With Virtual Isotropic Surface Probes

West

2018

Front. Neuroanat.

Self Cite

The space ball probe was fully described in the literature 15 years ago by Mouton et al. (2002). Since then, it has been used in a number of studies in the nervous system that focus on axon, dendrite, and capillary length. The length of structural parameters in tissues reflect functional aspects of the tissues. Here, some of the various applications of this methodology will be presented, along with a review of the salient features of the methodology that has resulted in new wave of quantitative morphological studies of length in the nervous system. The validity of the method is discussed in view of its widespread use along with insights into the problems associated with its application to histological tissue and future techniques for applying space balls.

J of Comparative Neurology

“…The probe has become known as a spaceball and is, together with its use, described in the following section. Well documented applications have been published by, for example, Calhoun, Mao, Roberts, and Rapp (2004), Shamy et al (2007), Gondré‐Lewis, Darius, Wang, and Allard (2016) or Nykjær Nikolajsen, Kotynski, Jensen, and West (2017),…”

Section: Length and Surface Estimatorsmentioning

confidence: 99%

Basic quantitative morphological methods applied to the central nervous system

Slomianka

2020

Generating numbers has become an almost inevitable task associated with studies of the morphology of the nervous system. Numbers serve a desire for clarity and objectivity in the presentation of results and are a prerequisite for the statistical evaluation of experimental outcomes. Clarity, objectivity, and statistics make demands on the quality of the numbers that are not met by many methods. This review provides a refresher of problems associated with generating numbers that describe the nervous system in terms of the volumes, surfaces, lengths, and numbers of its components. An important aim is to provide comprehensible descriptions of the methods that address these problems. Collectively known as designbased stereology, these methods share two features critical to their application. First, they are firmly based in mathematics and its proofs. Second and critically underemphasized, an understanding of their mathematical background is not necessary for their informed and productive application. Understanding and applying estimators of volume, surface, length or number does not require more of an organizational mastermind than an immunohistochemical protocol. And when it comes to calculations, square roots are the gravest challenges to overcome. Sampling strategies that are combined with stereological probes are efficient and allow a rational assessment if the numbers that have been generated are "good enough." Much may be unfamiliar, but very little is difficult. These methods can no longer be scapegoats for discrepant results but faithfully produce numbers on the material that is assessed. They also faithfully reflect problems that associated with the histological material and the anatomically informed decisions needed to generate numbers that are not only valid in theory. It is within reach to generate practically useful numbers that must integrate with qualitative knowledge to understand the function of neural systems.