Jacek Szczygielski

Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer’s disease

While axonopathy is a prominent feature in a variety of neurodegenerative diseases, it has been largely neglected in Alzheimer’s disease (AD), despite the observation of frequent motoric deficits in AD patients. In the present report we used transgenic mice overexpressing human mutant β-amyoid precursor protein (APP751SL) and presenilin-1 (PS1M146L) that exhibit elevated intraneuronal Aβ42 levels. We observed abundant age-dependent axonopathy in the spinal cord: axons immunopositive for ubiquitin in the dorsal column; axonal swellings (spheroids) which accumulated APP, neurofilament, and ubiquitin; as well as myelin ovoid structures, which serve as markers for nerve fiber degeneration in both white and gray matter. Both descending and ascending axonal tracts in white matter were affected. Neuritic plaques also developed in an age-dependent manner starting in the cervical region. Furthermore, early intraneuronal Aβ was detected in some but not all motor neurons before plaque formation. In the present APP/PS1 transgenic mouse model we could show for the first time that elevated intracellular Aβ levels lead to an axonopathy characterized by the formation of axonal spheroids and myelin ovoids. The same pathological alterations are known from AD patients or transgenic models overexpressing Tau or ApoE, however, these disturbances in axonal transport occur in the absence of any signs of concomitant Tau pathology. This strengthens the prevailing amyloid hypothesis as a primary trigger of AD-typical pathological alterations.

Traumatic brain injury : cause or risk of Alzheimer's disease? A review of experimental studies

Summary.Traumatic Brain Injury is the leading cause of death and disability among young individuals in our society. Moreover, according to some epidemiological studies, head trauma is one of the most potent environmental risk factors for subsequent development of Alzheimer’s disease. Interestingly, pathological features that are present also in Alzheimer’s disease (in particular deposition of beta-amyloid protein) were observed in traumatised brains already a few hours after the initial insult. The primary objective of this review is to present methodology and results of numerous recent human and animal studies dealing with this issue. Special emphasis was placed on head trauma experiments in transgenic mouse models of Alzheimer’s disease. We further evaluate the connection between traumatic brain insults and subsequent development of dementia and try to differentiate between primary and secondary pathological mechanisms.

The Effects of Selective Brain Hypothermia and Decompressive Craniectomy on Brain Edema After Closed Head Injury in Mice

Intractable brain edema remains one of the main causes of death after traumatic brain injury (TBI). Brain hypothermia and decompressive craniectomy have been considered as potential therapies. The goal of our experimental study was to determine if selective hypothermia in combination with craniectomy could modify the development of posttraumatic brain edema. Male CD-1 mice were anesthetized with halothane and randomly assigned into the following groups: sham-operated (n = 5), closed head injury (CHI) alone (n = 5), CHI followed by craniectomy at 1 h post-TBI (n = 5) and CHI + craniectomy and selective hypothermia (focal brain cooling using cryosurgery device) maintained for 5 h (n = 5). Animals were sacrificed at 7 h posttrauma and brains were removed, sagittally dissected and dried. The brain water content of separate hemispheres was calculated from the weight difference before and after drying. In the CHI alone group there was no significant increase in brain water content in both the ipsi- and contralateral hemispheres (80.59 +/- 1% and 78.74 +/- 0.9% in the CHI group vs. 79.31 +/- 0.7% and 79.01 +/- 0.3% in the sham group, respectively). Brain edema was significantly increased ipsilaterally in the trauma + craniectomy group (82.11 +/- 0.6%, p < 0.05), but not in the trauma + craniectomy + hypothermia group (81.52 +/- 1.1%, p > 0.05) as compared to the sham group (79.31 +/- 0.7%). These data suggest that decompressive craniectomy leads to an increase in brain water content after CHI. Additional focal hypothermia may be an effective approach in the treatment of posttraumatic brain edema.

Motion invariant contrast enhancement of optical imaging data in the gradient domain

Functional optical imaging (OI) of intrinsic signals (like blood oxygenation coupled reflection changes) and of extrinsic properties of voltage sensitive probes (like voltage-sensitive dyes (VSD)) forms a group of neuroimaging techniques that possess up to date highest temporal and spatial resolution on a meso-to macroscopic scale. An inherent problem of OI is a very low signal to noise ratio (SNR), which restricts the recordings to be completely motionless and requires detailed knowledge of the properties of the different noise sources. In our experiments we performed a durectomy and did not use an imaging chamber to allow us future joint electroencephalography-optical imaging (EEG-OI) measures, which resulted in movement artifacts. With the goal of motion compensation in OI recordings and magnification of signal changes, we present a novel processing pipeline, which is based on optic flow guided denoising and gradient domain tone mapping for spatiotemporal contrast enhancement.

Compensation of pulsation artifacts during optical imaging with and without cranial chamber

Functional Optical Imaging (OI) through the opened skull forms a group of Neuroimaging techniques characterized by a high temporal and spatial resolution on a meso-to macroscopic scale. State of the art OI experiments are generally difficult to execute, with a very timely surgical preparation preceding the experiment, that requires a skilled surgeon to mount a sealed imaging chamber onto the skull. The chamber reduces brain pulsation artifacts and swelling of the brain through movement restriction. In this work, we present preliminary results of a novel approach that does not rely on the usage of an imaging chamber with the goal to facilitate heavily the surgical animal preparation and to allow straightforward joint Electroencephalography - Optical Imaging recordings in the future. We carried out experiments to compare the movement restricting properties of the imaging chamber with the movement in a recording of an unconstrained and periodically irrigated brain. We used high-level image processing techniques to reduce brain pulsation artifacts and did a quantitative movement analysis of the recordings. Our results suggest that while recordings with imaging chamber show less sagittal movement, both with and without imaging chamber comprise the same lateral movements.

Motion reduction and multidimensional denoising in Voltage-sensitive Dye imaging

Optical Imaging using Voltage-sensitive Dyes is characterized by low fractional changes in fluorescent light intensity upon the application of a stimulus, which leads to slight value differences between pixels on an in-general noisy image sequence. The application of an anisotropic diffusion filtering scheme, in order to contribute to the denoising of the optical images, is proposed as one option to improve its quality and for a better understanding of the physiological processes they represent. We apply an image registration approach to compensate for motion artifacts, such that we do not need to mount a fixed cranial chamber onto the skull. In this work, electrical stimulation to the tibial nerve in a rat model was used to register evoke potentials, imaging the somatosensory cortex of the animal, which was previously stained with the RH1691 dye.

Changes in Posttraumatic Brain Edema in Craniectomy-Selective Brain Hypothermia Model Are Associated With Modulation of Aquaporin-4 Level

Both hypothermia and decompressive craniectomy have been considered as a treatment for traumatic brain injury. In previous experiments we established a murine model of decompressive craniectomy and we presented attenuated edema formation due to focal brain cooling. Since edema development is regulated via function of water channel proteins, our hypothesis was that the effects of decompressive craniectomy and of hypothermia are associated with a change in aquaporin-4 (AQP4) concentration. Male CD-1 mice were assigned into following groups (n = 5): sham, decompressive craniectomy, trauma, trauma followed by decompressive craniectomy and trauma + decompressive craniectomy followed by focal hypothermia. After 24 h, magnetic resonance imaging with volumetric evaluation of edema and contusion were performed, followed by ELISA analysis of AQP4 concentration in brain homogenates. Additional histopathological analysis of AQP4 immunoreactivity has been performed at more remote time point of 28d. Correlation analysis revealed a relationship between AQP4 level and both volume of edema (r2 = 0.45, p < 0.01, **) and contusion (r2 = 0.41, p < 0.01, **) 24 h after injury. Aggregated analysis of AQP4 level (mean ± SEM) presented increased AQP4 concentration in animals subjected to trauma and decompressive craniectomy (52.1 ± 5.2 pg/mL, p = 0.01; *), but not to trauma, decompressive craniectomy and hypothermia (45.3 ± 3.6 pg/mL, p > 0.05; ns) as compared with animals subjected to decompressive craniectomy only (32.8 ± 2.4 pg/mL). However, semiquantitative histopathological analysis at remote time point revealed no significant difference in AQP4 immunoreactivity across the experimental groups. This suggests that AQP4 is involved in early stages of brain edema formation after surgical decompression. The protective effect of selective brain cooling may be related to change in AQP4 response after decompressive craniectomy. The therapeutic potential of this interaction should be further explored.

Confocal Laser Endomicroscopy in Neurosurgery—An Alternative to Instantaneous Sections?

OBJECTIVE Intraoperative distinction of brain tumor from surrounding brain is a crucial challenge in neuro-oncologic surgery. We directly compared confocal laser endomicroscopy (CLE) findings with intraoperative instantaneous sections by the neuropathologist in a blinded fashion. METHODS The imaging device comprises a rigid endoscope with Hopkins rod lenses and a red wave length laser with a scanning depth of 80 μm. Brain tumor samples of 100 patients were investigated. Tissue samples were simultaneously investigated by the neuropathologist and with CLE. The tissue was not prepared or stained before CLE analysis. RESULTS CLE could be performed in all cases. Sensitivity for detection of a correct final diagnosis by CLE on site was 82%-90% for high-grade gliomas (26/32), low-grade gliomas (9/10), schwannomas (7/8), and meningiomas (28/34). Sensitivity of only 37% (6/16) was achieved for metastasis (6/16). CONCLUSIONS With intraoperative CLE, it is possible to obtain an on-site histologic diagnosis with a high sensitivity in many tumors. Although definitive histologic classification requires further neuropathologic investigation, these results show that CLE could fill the gap between tissue resection and microscopic analysis. This could ultimately help neurosurgeons to scan brain tissue for tumor remnants on a microscopic scale without having to resect it first. Further development of the device and further investigations are needed before this technique can become part of the neurosurgical routine in specific cases.

Advances and Technical Standards in Neurosurgery, Vol. 38

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Analysis of dominant neural activity clustering in laminar cortical processing of acoustic stimuli in rat utilizing von Mises-Fisher distribution

Despite decades of analytical research on sensory late evoked responses the information potential of evoked potentials is not yet exhausted. The influence of spectro-temporal synchronization dynamics in the sensory cortices on non-invasively recorded data remains still elusive. Evoked responses align reliably in phase during repetitive stimulus presentation, and are subject to attentional modulation. This indicates that phase alignment and thus response reliability is a key mechanism of (conscious) sensory processing. It is necessary to analyze underlying neural activity clustering in detail to gain a better understanding of attentional resource allocation. For this article we analyzed laminar activity clustering in Local Field Potentials (LFP) utilizing von Mises-Fisher distribution across 8 columnar aligned penetrating electrodes as a first approach to identify the role of increased response reliability as a mechanism of attentional neurodynamics.