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Showing papers by "Anders Björklund published in 2002"


Journal ArticleDOI
TL;DR: It is shown that nigral dopamine neurons are selectively vulnerable to high levels of either wild-type or mutant α-synuclein, pointing to a key role for α- Synuclein in the pathogenesis of Parkinson's disease.
Abstract: Recombinant adeno-associated viral vectors display efficient tropism for transduction of the dopamine neurons of the substantia nigra. Taking advantage of this unique property of recombinant adeno-associated viral vectors, we expressed wild-type and A53T mutated human α-synuclein in the nigrostriatal dopamine neurons of adult rats for up to 6 months. Cellular and axonal pathology, including α-synuclein-positive cytoplasmic inclusions and swollen, dystrophic neurites similar to those seen in brains from patients with Parkinson9s disease, developed progressively over time. These pathological alterations occurred preferentially in the nigral dopamine neurons and were not observed in other nondopaminergic neurons transduced by the same vectors. The degenerative changes were accompanied by a loss of 30–80% of the nigral dopamine neurons, a 40–50% reduction of striatal dopamine, and tyrosine hydroxylase levels that was fully developed by 8 weeks. Significant motor impairment developed in those animals in which dopamine neuron cell loss exceeded a critical threshold of 50–60%. At 6 months, signs of cell body and axonal pathology had subsided, suggesting that the surviving neurons had recovered from the initial insult, despite the fact that α-synuclein expression was maintained at a high level. These results show that nigral dopamine neurons are selectively vulnerable to high levels of either wild-type or mutant α-synuclein, pointing to a key role for α-synuclein in the pathogenesis of Parkinson9s disease. Targeted overexpression of α-synuclein in the nigrostriatal system may provide a new animal model of Parkinson9s disease that reproduces some of the cardinal pathological, neurochemical, and behavioral features of the human disease.

680 citations


Journal ArticleDOI
TL;DR: Dyskinesia severity was not related to the magnitude of graft-derived dopaminergic re-innervation, as judged by 18F-labeled 6-L-fluorodopa (FD) positron emission tomography (PET), indicating that off-phase dyskinesias probably did not result from excessive growth of grafted dopamine neurons.
Abstract: Severe dyskinesias during the 'off' phases (periods of increased Parkinson's disease (PD) disability) have been observed following intrastriatal transplantation of human embryonic mesencephalic tissue. Here we retrospectively analyzed 14 patients who were followed for up to 11 years after grafting, and found that dyskinesias (abnormal involuntary movements and postures) increased during postoperative off phases, but were generally of mild to moderate severity. Dyskinesia severity was not related to the magnitude of graft-derived dopaminergic re-innervation, as judged by (18)F-labeled 6-L-fluorodopa (FD) positron emission tomography (PET), indicating that off-phase dyskinesias probably did not result from excessive growth of grafted dopaminergic neurons.

428 citations


Journal ArticleDOI
TL;DR: These results are the first to demonstrate that selective and partial DA denervation in the sensorimotor part of the striatum can confer cellular and behavioral supersensitivity to L-DOPA, and that the phenomenology of L- DOPA-induced rat AIMs can be accounted for by the topography ofDA denervation within the caudate-putamen.

416 citations


Journal ArticleDOI
TL;DR: The results of the amphetamine-induced rotation suggested an initial partial protection followed by a complete recovery, whereas the spontaneous motor behaviors remained impaired, which may be explained by this extensive aberrant fiber sprouting in the downstream striatal target nuclei and/or decreased synthesis of dopamine in the striatum.

221 citations


Journal ArticleDOI
TL;DR: Patch-clamp techniques provide evidence that grafted neural progenitors can differentiate into morphologically mature pyramidal projection neurons, establish appropriate long-distance axonal projections, exhibit normal electrophysiological properties, and become functionally integrated into host cortical circuitry.
Abstract: In vitro expanded neural stem/progenitor cells can undergo region-specific differentiation after transplantation to the developing or adult brain, and display morphologies and markers characteristic of mature neurons. Here we have used patch-clamp techniques to explore whether grafted stem cells also can develop physiological properties of mature neurons and become functionally integrated within host neural circuitry. The immortalized neural progenitor cell line, RN33B, prelabeled with GFP by using a lentiviral vector, was transplanted into the cortex or hippocampus of neonatal rats. We found that the grafted GFP-positive cells differentiated into cells with morphological features of cortical or hippocampal pyramidal neurons, and that many of them had established appropriate cortico-thalamic and contralateral hippocampal connections, respectively, as revealed by retrograde tracing. Whole-cell patch-clamp recordings from grafted cells with morphological characteristics of pyramidal neurons showed that they were able to generate action potentials, and received functional excitatory and inhibitory synaptic inputs from neighboring cells. These data provide evidence that grafted neural progenitors can differentiate into morphologically mature pyramidal projection neurons, establish appropriate long-distance axonal projections, exhibit normal electrophysiological properties, and become functionally integrated into host cortical circuitry.

191 citations


Journal ArticleDOI
TL;DR: The extensive integration and differentiation of in vitro-expanded human neural progenitor cells indicate that multipotent progenitors are capable of responding in a regionally specific manner to cues present in the developing rat brain.

185 citations


Journal ArticleDOI
TL;DR: A large fraction of the grafted cells remained undifferentiated in a stem or progenitor cell stage as revealed by the expression of nestin and/or GFAP in the adult rat brain.

163 citations


Journal ArticleDOI
TL;DR: In this paper, the authors compared income inequality and income mobility in the Scandinavian countries and the United States during 1980-90 and found evidence of greater dispersion of first differences of relative earnings and income.
Abstract: This paper compares income inequality and income mobility in the Scandinavian countries and the United States during 1980–90. The results suggest that inequality is greater in the United States than in the Scandinavian countries and that this inequality ranking of countries remains unchanged when the accounting period of income is extended from one to eleven years. The pattern of mobility turns out to be remarkably similar, in the sense that the proportionate reduction in inequality from extending the accounting period of income is much the same. But we do find evidence of greater dispersion of first differences of relative earnings and income in the United States. Relative income changes are associated with changes in labor market and marital status in all four countries, but the magnitude of such changes are largest in the United States.

162 citations


Journal ArticleDOI
TL;DR: In this paper, the authors compared the long-run earnings between the United States and Nordic countries (Denmark, Finland, Norway and Sweden) and concluded that the family and community factors are more important determinants of long-term earnings in the U.S. than in the Nordic countries.
Abstract: The correlation in economic status among siblings is a useful “omnibus measure” of the overall impact of family and community factors on adult economic status. In this study we compare brother correlations in long-run (permanent) earnings between the United States, on one hand, and the Nordic countries (Denmark, Finland, Norway and Sweden) on the other. Our base case results, based on very similar sample criteria and definitions for all countries, show that this correlation is above 0.40 in the United States and in the range 0.14–0.26 in the Nordic countries. Even though these results turn out to be somewhat sensitive to some assumptions that have to be made, we conclude that the family and community factors are more important determinants of long-run earnings in the United States than in the Nordic countries.

151 citations


Journal ArticleDOI
TL;DR: Spared nigrostriatal fibers may convert l-dopa to dopamine and store and release dopamine in a more physiologically relevant manner in the denervated striatum to mediate better striatal output-dependent motor function in patients with Parkinson's disease.
Abstract: Intrastriatal delivery of the tyrosine hydroxylase gene by viral vectors is being explored as a tool for local delivery of L-dopa in animals with lesions of the nigrostriatal pathway. The functional effects reported using this approach have been disappointing, probably because the striatal L-dopa levels attained have been too low. In the present study, we have defined a critical threshold level of L-dopa, 1.5 pmol/mg of tissue, that has to be reached to induce any significant functional effects. Using new generation high-titer recombinant adeno-associated virus vectors, we show that levels of striatal L-dopa production exceeding this threshold can be obtained provided that tyrosine hydroxylase is coexpressed with the cofactor synthetic enzyme, GTP-cyclohydrolase-1. After striatal transduction with this combination of vectors, substantial functional improvement in both drug-induced and spontaneous behavior was observed in rats with either complete or partial 6-hydroxydopamine lesions of the nigrostriatal pathway. However, complete reversal of motor deficits occurred only in animals in which part of the striatal dopamine innervation was left intact. Spared nigrostriatal fibers thus may convert L-dopa to dopamine and store and release dopamine in a more physiologically relevant manner in the denervated striatum to mediate better striatal output-dependent motor function. We conclude that intrastriatal L-dopa delivery may be a viable strategy for treatment and control of adverse side effects associated with oral L-dopa therapy such as on-off fluctuations and drug-induced dyskinesias in patients with Parkinson's disease.

148 citations


Journal ArticleDOI
TL;DR: Striatal delivery of rLV-GDNF efficiently protected the nigral dopamine neurons and their projection, against the 6-OHDA lesion (65–77% of intact side).
Abstract: We used a recombinantlentiviral vector (rLV) for gene delivery of GDNF to the striatum, and assessed its neuroprotective eiects in the intrastriatal 6 -hydroxydopamine (6 -OHDA) lesion model.The level of GDNF expression obtained with the rLV-GDNF vector was dose-related and ranged between 0.9^9.3 ng/mg tissue in the transduced striatum, as determined by ELISA, and 0.2^3.0 ng/mg tissue were detected in the ipsilateral substantia nigra (SN), due to anterograde transport of the GDNF protein. GDNF expression was apparentat4 days and maint ained for � 8 months after injection. Striatal delivery of rLV-GDNF e⁄ciently protected the nigral dopamine (DA) neurons and their projection, against the 6 -OHDA lesion (65^77% of intact side). Sprouting of the lesioned axons was observed along the nigrostriatal pathway, precisely corresponding to the areas containing anterogradely transported GDNF.NeuroReport13:75^ 82 � c 2002 Lippincott Williams & Wilkins.

Journal ArticleDOI
TL;DR: The present findings suggest that precursor cells in neurosphere cultures, derived from distinct subregions of the embryonic telencephalon, maintain at least certain aspects of their molecular specification, even after significant expansion in vitro.

Journal ArticleDOI
TL;DR: The ability of the grafted RN33B cells to undergo region-specific differentiation into highly specialized types of forebrain projection neurons and establish connections with appropriate targets suggests that cues present in the microenvironment of the neonatal rat brain can effectively guide the development of immature progenitors, also in the absence of ongoing neurogenesis.

Posted Content
TL;DR: In this article, the authors analyzed whether the commonly found negative relationship between parental separation in childhood and educational outcomes is causal or mainly due to selection, using data on 100,000 Swedish full biological siblings, born in 1951-64, and perform cross-section and sibling-difference estimations.
Abstract: This article analyzes whether the commonly found negative relationship between parental separation in childhood and educational outcomes is causal or mainly due to selection. We use data on about 100,000 Swedish full biological siblings, born in 1951-64, and perform cross-section and sibling-difference estimations. Outcomes are measured as educational attainment in 1996. Our cross-section analysis show the expected negative and significant relationship, while the relationship is not significant, though precisely estimated, in the siblingdifference analysis. This finding was robust to the sensitivity tests performed and is consistent with selection, rather than causation, being the explanation for the negative relationship.

Book ChapterDOI
01 Jan 2002
TL;DR: This chapter will summarise the different GDNF induced effects observed and discuss how they may vary depending on which lesion model have been used as well as the treatment regime applied for GDNF.
Abstract: Glial cell line-derived neurotrophic factor (GDNF) have been found to be a very potent neurotrophic factor for nigrostriatal dopamine neurons in vitro and in vivo. Intracerebral administration of GDNF can produce three principal structural effects. (1) increased survival of lesioned adult DA neurons, (2) sprouting of new fibers dopamine fibers and (3) pharmacological effects related to altered synthesis, turnover and metabolism of dopamine. These effects may in turn promote restoration of function in animals models of Parkinson’s disease. This chapter will summarise the different GDNF induced effects observed and discuss how they may vary depending on which lesion model have been used as well as the treatment regime applied for GDNF.