Brain Banking – Bioethical Implications

"Novel biotechnologies like brain banking pose a challenge in neurodegenerative diseases research, being not only a step towards a better understanding for these diseases, but also from a bioethical point of view. Brain banks collect tissue for research purposes from deceased persons suffering from neurodegenerative diseases such as Parkinson’s or Alzheimes’s disease. In order to improve the quality in this research field, confidentiality and a detailed informed consent are aspects that should be emphasized. Moreover, given the fact that the brain collecting takes place during an autopsy, legal aspects also play an important role, hence a legal frame is also needed. The role of the deceased’s family should also be taken into account, especially when and how they can decide if the autopsy can be performed in the first place. The research participant should sign a detailed informed consent that must remain the research basis to which extent the collected data should be disclosed. Finally, only a framework of bioethical and legal norms can improve the quality of brain banking research. A comprehensive perspective for brain banking from obtaining, processing, and storage of brain material to bioethical and legal aspects should increase the scarce sapling of brain banking. "

DNAJB6b is Downregulated in Synucleinopathies

Background: α-synuclein (α-syn) aggregation contributes to the progression of multiple neurodegenerative diseases. We recently found that the isoform b of the co-chaperone DNAJB6 is a strong suppressor of a-syn aggregation in vivo and in vitro. However, nothing is known about the role of the endogenous isoform b of DNAJB6 (DNAJB6b) in health and disease, due to lack of specific antibodies. Objective: Here we generated a novel anti-DNAJB6b antibody to analyze the localization and expression this isoform in cells, in tissue and in clinical material. Methods: To address this we used immunocytochemistry, immunohistochemistry, as well as a novel quantitative DNAJB6 specific ELISA method. Results: The endogenous protein is mainly expressed in the cytoplasm and in neurites in vitro, where it is found more in dendrites than in axons. We further verified in vivo that DNAJB6b is expressed in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), which is a neuronal subpopulation highly sensitive to α-syn aggregation, that degenerate to a large extend in patients with Parkinson’s disease (PD) and multiple system atrophy (MSA). When we analyzed the expression levels of DNAJB6b in brain material from PD and MSA patients, we found a downregulation of DNAJB6b by use of ELISA based quantification. Interestingly, this was also true when analyzing tissue from patients with progressive supranuclear palsy, a taupathic atypical parkinsonian disorder. However, the total level of DNAJB6 was upregulated in these three diseases, which may indicate an upregulation of the other major isoform of DNAJB6, DNAJB6a. Conclusion: This study shows that DNAJB6b is downregulated in several different neurodegenerative diseases, which makes it an interesting target to further investigate in relation to amyloid protein aggregation and disease progression.

First Sequencing of Caprine Mdr1 (Abcb1) mRNA Due to Suspected Neurological Adverse Drug Reaction in a Thuringian Goat Following Extra-Label Use of Doramectin

The multidrug resistance gene MDR1 encodes for an efflux transporter called P-glycoprotein (P-gp). In the canine Mdr1 gene, a nonsense mutation was identified in certain dog breeds causing increased drug sensitivity to various P-gp substrates such as antiparasitic macrocyclic lactones. Symptoms of neurologic toxicity include ataxia, depression, salivation, tremor, apparent blindness, and mydriasis. In the current report, a Thuringian goat developed similar neurological signs after treatment with doramectin, a compound from the macrocyclic lactone class. Therefore, Mdr1 might be defective in this individual goat. For diagnostic purposes, sequencing of the complete mRNA transcript coding for caprine Mdr1 was performed to investigate a potential missense mutation. The Mdr1 transcripts of two related goats without drug sensitivity were also sequenced to allow differential diagnosis and were compared to the suspected drug-sensitive goat. The only position where the Mdr1 sequence from the suspected drug-sensitive goat differed was in the 3′-untranslated region, being a heterozygous single nucleotide polymorphism c.3875C>A. It can be suspected that this variant affects the expression level, stability, or translation efficiency of the Mdr1 mRNA transcript and therefore might be associated with the suspected drug sensitivity. To clarify this, further studies are needed, particularly investigating the Mdr1 mRNA and protein expression levels from brain material of affected goats. In conclusion, Mdr1 variants may exist not only in dogs, but also in individual goats. The current report provides the first Mdr1 mRNA transcript sequence of a goat and therefore represents the basis for more detailed Mdr1 sequence and expression analyses.

Density and Mechanical Properties of Selective Silicon Materials to Produce 3D Printed Paediatric Brain Model

This study presents a step towards exploring the possibility of using silicon materials as a surrogate to produce a multi-material 3D printed soft silicone brain model to be used in the investigation of Traumatic Brain Injury (TBI) in paediatric populations. Silicone represents a popular choice of material due to its viscoelastic properties, 3D printability, and capability to be tuned to possess different properties. Dynamic oscillatory shear tests were carried out for seven types of silicon materials at three different speeds against a different range of frequencies. The mechanical parameters response has been ranked on, which is the most appropriate to try. It also agrees with the range of reported paediatric brain tissue imitating grey and white matter as a surrogate brain material. Utilising of silicone for 3D printing represents a new approach to fabricate surrogate models that closely mimic biofidelic features and advance the medical engineering discipline.

Biomechanical Analysis of the Sensitivity of Brain Tissue Responses to FE Head Models in the Study of Impact-Induced TBI

A numerical investigation is conducted on the injury-related biomechanical parameters of the human head under blunt impacts. The objective of this research is twofold; first to understand the role of the employed finite element (FE) head model — with its specific components, shape, size, material properties, and mesh size — in predicting tissue responses of the brain, and second to investigate the fidelity of pressure response in validating FE head models. Accordingly, two independently established and validated FE head models are impacted in two directions under two impact severities and their predicted responses in terms of intracranial pressure (ICP) and shear stress are compared. The coup-counter ICP peak values are less sensitive to head model, mesh size, and the brain material. In all cases, maximum ICPs occur on the outer surface, vanishing linearly toward the center of the brain. Hence, it is concluded that different head models may simply reproduce the results of ICP variations due to impact. Shear stress prediction, however, is mainly affected by the head model, direction and severity of impact, and the brain material.

Effects of Alzheimer’s disease and formalin fixation on the different mineralised-iron forms in the human brain

Iron accumulation in the brain is a phenomenon common to many neurodegenerative diseases, perhaps most notably Alzheimer’s disease (AD). We present here magnetic analyses of post-mortem brain tissue of patients who had severe Alzheimer’s disease, and compare the results with those from healthy controls. Isothermal remanent magnetization experiments were performed to assess the extent to which different magnetic carriers are affected by AD pathology and formalin fixation. While Alzheimer’s brain material did not show higher levels of magnetite/maghemite nanoparticles than corresponding controls, the ferrihydrite mineral, known to be found within the core of ferritin proteins and hemosiderin aggregates, almost doubled in concentration in patients with Alzheimer’s pathology, strengthening the conclusions of our previous studies. As part of this study, we also investigated the effects of sample preparation, by performing experiments on frozen tissue as well as tissue which had been fixed in formalin for a period of 5 months. Our results showed that the two different preparations did not critically affect the concentration of magnetic carriers in brain tissue, as observable by SQUID magnetometry.