Showing papers by "Anders Björklund published in 2017"

Modeling Parkinson’s disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain

Abstract: Although a causative role of α-synuclein (α-syn) is well established in Parkinson’s disease pathogenesis, available animal models of synucleinopathy do not replicate the full range of cellular and behavioral changes characteristic of the human disease. This study was designed to generate a more faithful model of Parkinson’s disease by injecting human α-syn fibril seeds into the rat substantia nigra (SN), in combination with adenoassociated virus (AAV)-mediated overexpression of human α-syn, at levels that, by themselves, are unable to induce acute dopamine (DA) neurodegeneration. We show that the ability of human α-syn fibrils to trigger Lewy-like α-synuclein pathology in the affected DA neurons is dramatically enhanced in the presence of elevated levels of human α-syn. This synucleinopathy was fully developed already 10 days after fibril injection, accompanied by progressive degeneration of dopaminergic neurons in SN, neuritic swelling, reduced striatal DA release, and impaired motor behavior. Moreover, a prominent inflammatory response involving both activation of resident microglia and infiltration of CD4+ and CD8+ T lymphocytes was observed. Hypertrophic microglia were found to enclose or engulf cells and processes containing Lewy-like α-syn aggregates. α-Syn aggregates were also observed inside these cells, suggesting transfer of phosphorylated α-syn from the affected nigral neurons. The nigral pathology triggered by fibrils in combination with AAV-mediated overexpression of α-syn reproduced many of the cardinal features of the human disease. The short time span and the distinct sequence of pathological and degenerative changes make this combined approach attractive as an experimental model for the assessment of neuroprotective and disease-modifying strategies.

Replacing Dopamine Neurons in Parkinson's Disease: How did it happen?

Abstract: The efforts to develop a dopamine cell replacement therapy for Parkinson's disease have spanned over more than three decades. Based on almost 10 years of transplantation studies in animal models, the first patients receiving grafts of fetal-derived dopamine neuroblasts were operated in Lund in 1987. Over the following two decades, a total of 18 patients were transplanted and followed closely by our team with mixed but also very encouraging results. In this article we tell the story of how the preclinical and clinical transplantation program in Lund evolved. We recall the excitement when we obtained the first evidence for survival and function of transplanted neurons in the diseased human brain. We also remember the setbacks that we have experienced during these 30 years and discuss the very interesting developments that are now taking place in this exciting field.

Mechanisms and use of neural transplants for brain repair.

Abstract: Under appropriate conditions, neural tissues transplanted into the adult mammalian brain can survive, integrate, and function so as to influence the behavior of the host, opening the prospect of repairing neuronal damage, and alleviating symptoms associated with neuronal injury or neurodegenerative disease. Alternative mechanisms of action have been postulated: nonspecific effects of surgery; neurotrophic and neuroprotective influences on disease progression and host plasticity; diffuse or locally regulated pharmacological delivery of deficient neurochemicals, neurotransmitters, or neurohormones; restitution of the neuronal and glial environment necessary for proper host neuronal support and processing; promoting local and long-distance host and graft axon growth; formation of reciprocal connections and reconstruction of local circuits within the host brain; and up to full integration and reconstruction of fully functional host neuronal networks. Analysis of neural transplants in a broad range of anatomical systems and disease models, on simple and complex classes of behavioral function and information processing, have indicated that all of these alternative mechanisms are likely to contribute in different circumstances. Thus, there is not a single or typical mode of graft function; rather grafts can and do function in multiple ways, specific to each particular context. Consequently, to develop an effective cell-based therapy, multiple dimensions must be considered: the target disease pathogenesis; the neurodegenerative basis of each type of physiological dysfunction or behavioral symptom; the nature of the repair required to alleviate or remediate the functional impairments of particular clinical relevance; and identification of a suitable cell source or delivery system, along with the site and method of implantation, that can achieve the sought for repair and recovery.

The Contribution of Early‐life Versus Labour Market Factors to Intergenerational Income Persistence: A Comparison of the UK and Sweden

Abstract: We explore whether differences in intergenerational income mobility between the UK and Sweden show up early in life, finding stronger associations between parental income and birthweight, height and school performance in the UK. We investigate whether these differentials can account for the country difference in income mobility. While differences in the associations in birthweight and height are too weak to matter, school performance does account for a substantial part of this difference. However, country differences in the earnings returns to these skills are at least as important as the differences in the link between parental income and skills.

Early health and school outcomes for children with lesbian parents : evidence from Sweden

Abstract: Sweden was early to legalize same-sex partnership (1995), to allow same-sex couples to adopt children (2003), and to offer same-sex couples fertility treatment through the national health system (2 ...

Early Health and School Outcomes for Children with Lesbian Parents: Evidence from Sweden

Abstract: Sweden was early to legalize same-sex partnership (1995), to allow same-sex couples to adopt children (2003), and to offer same-sex couples fertility treatment through the national health system (2005). Using population data, we identify children of lesbian parents as those whose biological mother was a registered same-sex partner no later than six months after the child's birth. The number of such children increased markedly from 1995 to 2010 with a total of 750 children for the whole period. We find that boys and girls with lesbian parents had 2.4 percent lower birth weight than other children, a difference that is statistically significant from zero at the 5 percent level. Girls, but not boys, also have a higher probability of having a low birth weight. We follow these children until age ten and observe diseases of the respiratory system. Boys with lesbian parents have a significantly lower probability of such diseases (-3.4 percentage points), and girls with lesbian parents an insignificantly higher probability (+2.4 percentage points). Our analysis of school outcomes at age ten uses a small sample so precision is low. The point estimates show that boys with lesbian parents outperform other children by around 10 percentiles higher test scores in Math and Swedish. These differences are barely significant, while estimates for girls are lower and not significant. For all outcomes, we find that children with lesbian parents benefit from their mother's socio-economic status, whereas they suffer in terms of birth weight from having been exposed to fertility treatment.