Carlos Juri | Pontificia Universidad Catolica de Chile (original) (raw)

Papers by Carlos Juri

Holmes tremor is an infrequent clinical syndrome characterized by unilateral rest, postural, and ... more Holmes tremor is an infrequent clinical syndrome characterized by unilateral rest, postural, and action tremor often secondary to a brain lesion. We herein report an interesting case of Holmes tremor studied with PET and F-PR04.MZ, a new high-affinity radioligand for dopamine transporters, currently under investigation at our center. F-PR04.MZ-PET can be useful to study the integrity of the nigrostriatal dopaminergic system to improve diagnosis and therapeutic outcome in patients with Holmes tremor and Parkinson disease.

Las enfermedades neurodegenerativas son un importante problema de salud pública a nivel mundial. ... more Las enfermedades neurodegenerativas son un importante problema de salud pública a nivel mundial. Actualmente, no existen herramientas para el diagnóstico precoz de estas

Parkinson´s disease(PD) is characterize by a progressive death of dopaminergic neurons in the sub... more Parkinson´s disease(PD) is characterize by a progressive death of dopaminergic neurons in the substantia nigra causing a dopamine depletion in the striatum, which is associated with metabolic compensatory changes. The rat with 6-hydroxydopamine (6-OHDA)-induced lesion in one hemisphere has been widely used as a model of PD. However, the series of pathophysiological and compensatory mechanisms associated with the lesion are not well understood. We performed a neuroimaging study aiming to define the functional changes associated with dopamine striatal depletion. Sprague-Dawley rats were unilaterally lesion using 4µg/4µl and 8µg/4µl of 6-OHDA by intracraneal injection in the median forebrain bundle. PET imaging was performed using a monoaminergic (11C-Dihydrotetrabenazine; 11C-DTBZ) and a metabolic (18F-fluorodeoxyglucose; 18F-FDG) radiotracer and conducted 1 day and 1, 2 , 3 and 6 weeks after the lesion in each animal. Analysis based on regions of interest was done for 11C-DTBZ PET (s...

Neurobiology of Disease, 2015

Carbon-11 labeled dihydrotetrabenazine ((11)C-DTBZ) binds to the vesicular monoamine transporter ... more Carbon-11 labeled dihydrotetrabenazine ((11)C-DTBZ) binds to the vesicular monoamine transporter 2 and has been used to assess nigro-striatal integrity in animal models and patients with Parkinson's disease. Here, we applied (11)C-DTBZ positron emission tomography (PET) to obtain longitudinally in-vivo assessment of striatal dopaminergic loss in the classic unilateral and in a novel bilateral 6-hydroxydopamine (6-OHDA) lesion rat model. Forty-four Sprague-Dawley rats were divided into 3 sub-groups: 1. 6-OHDA-induced unilateral lesion in the medial forebrain bundle, 2. bilateral lesion by injection of 6-OHDA in the third ventricle, and 3. vehicle injection in either site. (11)C-DTBZ PET studies were investigated in the same animals successively at baseline, 1, 3 and 6weeks after lesion using an anatomically standardized volumes-of-interest approach. Additionally, 12 rats had PET and Magnetic Resonance Imaging to construct a new (11)C-DTBZ PET template. Behavior was characterized by rotational, catalepsy and limb-use asymmetry tests and dopaminergic striatal denervation was validated post-mortem by immunostaining of the dopamine transporter (DAT). (11)C-DTBZ PET showed a significant decrease of striatal binding (SB) values one week after the unilateral lesion. At this point, there was a 60% reduction in SB in the affected hemisphere compared with baseline values in 6-OHDA unilaterally lesioned animals. A 46% symmetric reduction over baseline SB values was found in bilaterally lesioned rats at the first week after lesion. SB values remained constant in unilaterally lesioned rats whereas animals with bilateral lesions showed a modest (22%) increase in binding values at the 3rd and 6th weeks post-lesion. The degree of striatal dopaminergic denervation was corroborated histologically by DAT immunostaining. Statistical analysis revealed a high correlation between (11)C-DTBZ PET SB and striatal DAT immunostaining values (r=0.95, p<0.001). The data presented here indicate that (11)C-DTBZ PET may be used to ascertain changes occurring in-vivo throughout the evolution of nigro-striatal dopaminergic neurodegeneration, mainly in the unilateral 6-OHDA lesion rat.

Normalization of neuroimaging studies to a stereotaxic space allows the utilization of standard v... more Normalization of neuroimaging studies to a stereotaxic space allows the utilization of standard volumes of interest (VOIs) and voxel-based analysis (SPM). Such spatial normalization of PET and MRI studies requires a high quality template image. The aim of this study was to create new MRI and PET templates of 18 F-DOPA and 11 C-(+)-α-dihydrotetrabenazine ( 11 C-DTBZ) of the Macaca fascicularis brain, an important animal model of Parkinson's disease. MRI template was constructed as a smoothed average of the scans of 15 healthy animals, previously transformed into the space of one representative MRI. In order to create the PET templates, 18 F-DOPA and 11 C-DTBZ PET of the same subjects were acquired in a dedicated small animal PET scanner and transformed to the created MRI template space. To validate these templates for PET quantification, parametric values obtained with a standard VOI-map applied after spatial normalization to each template were statistically compared to results computed using individual VOIs drawn for each animal. The high correlation between both procedures validated the utilization of all the templates, improving the reproducibility of PET analysis. To prove the utility of the templates for voxel-based quantification, dopamine striatal depletion in a representative monkey treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was assessed by SPM analysis of 11 C-DTBZ PET. A symmetric reduction in striatal 11 C-DTBZ uptake was detected in accordance with the induced lesion. In conclusion, templates of M. fascicularis brain have been constructed and validated for reproducible and automated PET quantification. All templates are electronically available via the internet.

Neurobiology of Disease, 2010

Dopaminergic depletion in the nigrostriatal system is the neurochemical hallmark of Parkinson's d... more Dopaminergic depletion in the nigrostriatal system is the neurochemical hallmark of Parkinson's disease (PD). Although numerous efforts have been made to determine the evolution of dopaminergic depletion in PD, "in vivo" data concerning the stages of this process are still scarce. We evaluated 6-[18F]-fluoro-L-DOPA ( 18 F-DOPA) and 11C-(+)-α-dihydrotetrabenazine ( 11 C-DTBZ) using PET in a model of chronically MPTPinduced parkinsonism in non-human primates. Methods: Sixty-seven cynomolgus monkeys (Macaca fascicularis) were included in the study. Progressive parkinsonism was induced by repeated administration of small doses of MPTP (iv) over several months. Animals were classified as controls, asymptomatic, recovered (having exhibited parkinsonian features transiently) and stable parkinsonian, according to their motor status. Analysis of striatal dopaminergic activity was conducted by regions of interest (ROI) and statistical parametric mapping (SPM) over normalized parametric images. Results: A progressive loss of striatal uptake was evident among groups for both radiotracers, which correlated significantly with the clinical motor status. Changes occurred earlier, i.e. in the less affected stages, with 11 C-DTBZ. Similar results were achieved by ROI and SPM analysis. Uptake was similar with both radiotracers for the asymptomatic and recovered groups. Conclusions: Serial assessment with 18 F-DOPA and 11 C-DTBZ PETs provides an effective approach to evaluate evolution of dopaminergic depletion in monkeys with MPTP-induced parkinsonism. This approach could be useful to perform studies aiming to test the effect of early therapeutic intervention and putative neuroprotective treatments.

Movement Disorders, 2010

have to be congratulated for their hypothesis on PD pathogenesis. They suggest that the sequence ... more have to be congratulated for their hypothesis on PD pathogenesis. They suggest that the sequence of the brain changes in PD follows specific and repeatable patterns in all cases, as well as that a prion-like process underlies neurodegeneration. These ideas could explain several features of PD, such as the high prevalence of olfactory, autonomic, or sleep abnormalities. However, any pathogenic hypothesis should also explain:

Journal of the Neurological Sciences, 2010

The diagnosis of Parkinson's disease (PD) is stil... more The diagnosis of Parkinson's disease (PD) is still based on the recognition of the cardinal motor features. However, it is now recognized that non-motor manifestations (NMM) may actually precede the emergence of motor manifestations. NMM are very frequently present in the overall population of PD patients and are a major determinant of their quality of life. In this article we discuss the origin of sensory manifestations in PD, particularly focus on pain mechanisms, which is the most frequent and better studied NMM. Analysis of experimental and clinical data reveals that the basal ganglia (BG) indeed have an anatomo-functional organization which sustains sensory functions. In addition, the dopaminergic system is also engaged in the modulation and integration of sensory information and the response to pain. In patients with PD, pain is often related with motor fluctuations and dyskinesias induced by dopaminergic treatments, which suggest some common mechanisms with the origin of motor complications in PD. Clinically, sensory manifestations are often disturbing and poorly treated and may occasionally become a major cause of disability for PD patients. Thus, more clinical and basic studies are warranted to clarify pain mechanisms in PD, with the aim of achieving better treatments.

European Journal of Nuclear Medicine and Molecular Imaging, 2011

Although specific PET scanners have been developed for small animals, spatial resolution remains ... more Although specific PET scanners have been developed for small animals, spatial resolution remains one of the most critical technical limitations, particularly in the evaluation of the rodent brain. The purpose of the present study was to examine the reliability of voxel-based statistical analysis (SPM) applied to 18 Ffluorodeoxyglucose ( 18 F-FDG) PET images of the rat brain, acquired on a small

Clinical Neuropharmacology, 2005

Quetiapine is an atypical antipsychotic with sedative properties frequently used to treat halluci... more Quetiapine is an atypical antipsychotic with sedative properties frequently used to treat hallucinations and psychosis in Parkinson disease (PD). The objective of this trial is to evaluate quetiapine for insomnia in nonpsychotic PD patients. Fourteen consecutive PD patients with frequent insomnia and without psychotic symptoms were treated openly for 12 weeks with a single evening dose of quetiapine. The dose was adjusted according to clinical improvement and tolerance. The severity of insomnia was assessed using the Pittsburgh Sleep Quality Index (PSQI), daytime sleepiness was evaluated with the Epworth Sleep Scale (ESS), and motor performance was evaluated using the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). All evaluations were done before and 1, 2, and 3 months after initiation of treatment. Total PSQI basal scores were 13.6 6 3.7 points. The PSQI score improved in 11 patients and was reduced by 3.8 6 3.9 points by the end of the study (P , 0.01). The ESS score was reduced by 4.3 6 3.7 points (P , 0.01). The mean quetiapine dose was 31.9 mg/day. No significant change was observed in the motor scale. Two patients were discontinued due to nonserious adverse effects. These results suggest that quetiapine may be a safe and effective treatment of insomnia in PD patients. Doubleblind studies will probably confirm these findings.

Biology of Blood and Marrow Transplantation, 2010

It is thought that the ability of human mesenchymal stem cells (hMSC) to deliver neurotrophic fac... more It is thought that the ability of human mesenchymal stem cells (hMSC) to deliver neurotrophic factors might be potentially useful for the treatment of neurodegenerative disorders. The aim of the present study was to characterize signals and/or molecules that regulate brain-derived neurotrophic factor (BDNF) protein expression/ delivery in hMSC cultures and evaluate the effect of epigenetically generated BDNF-secreting hMSC on the intact and lesioned substantia nigra (SN). We tested 4 different culture media and found that the presence of fetal bovine serum (FBS) decreased the expression of BDNF, whereas exogenous addition of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) to serum-free medium was required to induce BDNF release (125 6 12 pg/day/10 6 cells). These cells were called hM(N)SC. Although the induction medium inhibited the expression of alpha smooth muscle actin (ASMA), an hMSC marker, and increased the nestinpositive subpopulation of hMSC cultures, the ability to express BDNF was restricted to the nestin-negative subpopulation. One week after transplantation into the SN, the human cells integrated into the surrounding tissue, and some showed a dopaminergic phenotype. We also observed the activation of Trk receptors for neurotrophic factors around the implant site, including the BDNF receptor TrkB. When we transplanted these cells into the unilateral lesioned SN induced by striatal injection of 6-hydroxydopamine (6-OHDA), a significant hypertrophy of nigral tyrosine hydroxylase (TH) 1 cells, an increase of striatal TH-staining and stabilization of amphetamine-induced motor symptoms were observed. Therefore, hMSC cultures exposed to the described induction medium might be highly useful as a vehicle for neurotrophic delivery to the brain and specifically are strong candidates for future therapeutic application in Parkinson's disease.

Arquivos de Neuro-Psiquiatria, 2008

Parkinson's disease (PD) is a neurodegenerative disorder, predominantly characterized by the pres... more Parkinson's disease (PD) is a neurodegenerative disorder, predominantly characterized by the presence of motor symptoms. However, the non motor manifestations (NMM) are a frequent complaint in the PD patients. There is a lack of information about the risk factors associated with the NMM in these patients. The aim of this study is to evaluate the prevalence of the more common NMM in a population of PD patients and to determine the features associated with its development. We studied 124 ambulatory PD patients. NMM were defined by the presence of neuropsychiatric manifestations, cognitive disorder, autonomic dysfunction or sleep related problems. In a multivariate analysis we found that the years of evolution of the PD and the presence of cognitive dysfunction are the risk factors for the neuropsychiatric and autonomic manifestations, whereas axial impairment is a risk factor for cognitive disorders and dyskinesias is for sleep related problems.

Holmes tremor is an infrequent clinical syndrome characterized by unilateral rest, postural, and ... more Holmes tremor is an infrequent clinical syndrome characterized by unilateral rest, postural, and action tremor often secondary to a brain lesion. We herein report an interesting case of Holmes tremor studied with PET and F-PR04.MZ, a new high-affinity radioligand for dopamine transporters, currently under investigation at our center. F-PR04.MZ-PET can be useful to study the integrity of the nigrostriatal dopaminergic system to improve diagnosis and therapeutic outcome in patients with Holmes tremor and Parkinson disease.

Las enfermedades neurodegenerativas son un importante problema de salud pública a nivel mundial. ... more Las enfermedades neurodegenerativas son un importante problema de salud pública a nivel mundial. Actualmente, no existen herramientas para el diagnóstico precoz de estas

Parkinson´s disease(PD) is characterize by a progressive death of dopaminergic neurons in the sub... more Parkinson´s disease(PD) is characterize by a progressive death of dopaminergic neurons in the substantia nigra causing a dopamine depletion in the striatum, which is associated with metabolic compensatory changes. The rat with 6-hydroxydopamine (6-OHDA)-induced lesion in one hemisphere has been widely used as a model of PD. However, the series of pathophysiological and compensatory mechanisms associated with the lesion are not well understood. We performed a neuroimaging study aiming to define the functional changes associated with dopamine striatal depletion. Sprague-Dawley rats were unilaterally lesion using 4µg/4µl and 8µg/4µl of 6-OHDA by intracraneal injection in the median forebrain bundle. PET imaging was performed using a monoaminergic (11C-Dihydrotetrabenazine; 11C-DTBZ) and a metabolic (18F-fluorodeoxyglucose; 18F-FDG) radiotracer and conducted 1 day and 1, 2 , 3 and 6 weeks after the lesion in each animal. Analysis based on regions of interest was done for 11C-DTBZ PET (s...

Neurobiology of Disease, 2015

Carbon-11 labeled dihydrotetrabenazine ((11)C-DTBZ) binds to the vesicular monoamine transporter ... more Carbon-11 labeled dihydrotetrabenazine ((11)C-DTBZ) binds to the vesicular monoamine transporter 2 and has been used to assess nigro-striatal integrity in animal models and patients with Parkinson's disease. Here, we applied (11)C-DTBZ positron emission tomography (PET) to obtain longitudinally in-vivo assessment of striatal dopaminergic loss in the classic unilateral and in a novel bilateral 6-hydroxydopamine (6-OHDA) lesion rat model. Forty-four Sprague-Dawley rats were divided into 3 sub-groups: 1. 6-OHDA-induced unilateral lesion in the medial forebrain bundle, 2. bilateral lesion by injection of 6-OHDA in the third ventricle, and 3. vehicle injection in either site. (11)C-DTBZ PET studies were investigated in the same animals successively at baseline, 1, 3 and 6weeks after lesion using an anatomically standardized volumes-of-interest approach. Additionally, 12 rats had PET and Magnetic Resonance Imaging to construct a new (11)C-DTBZ PET template. Behavior was characterized by rotational, catalepsy and limb-use asymmetry tests and dopaminergic striatal denervation was validated post-mortem by immunostaining of the dopamine transporter (DAT). (11)C-DTBZ PET showed a significant decrease of striatal binding (SB) values one week after the unilateral lesion. At this point, there was a 60% reduction in SB in the affected hemisphere compared with baseline values in 6-OHDA unilaterally lesioned animals. A 46% symmetric reduction over baseline SB values was found in bilaterally lesioned rats at the first week after lesion. SB values remained constant in unilaterally lesioned rats whereas animals with bilateral lesions showed a modest (22%) increase in binding values at the 3rd and 6th weeks post-lesion. The degree of striatal dopaminergic denervation was corroborated histologically by DAT immunostaining. Statistical analysis revealed a high correlation between (11)C-DTBZ PET SB and striatal DAT immunostaining values (r=0.95, p<0.001). The data presented here indicate that (11)C-DTBZ PET may be used to ascertain changes occurring in-vivo throughout the evolution of nigro-striatal dopaminergic neurodegeneration, mainly in the unilateral 6-OHDA lesion rat.

Normalization of neuroimaging studies to a stereotaxic space allows the utilization of standard v... more Normalization of neuroimaging studies to a stereotaxic space allows the utilization of standard volumes of interest (VOIs) and voxel-based analysis (SPM). Such spatial normalization of PET and MRI studies requires a high quality template image. The aim of this study was to create new MRI and PET templates of 18 F-DOPA and 11 C-(+)-α-dihydrotetrabenazine ( 11 C-DTBZ) of the Macaca fascicularis brain, an important animal model of Parkinson's disease. MRI template was constructed as a smoothed average of the scans of 15 healthy animals, previously transformed into the space of one representative MRI. In order to create the PET templates, 18 F-DOPA and 11 C-DTBZ PET of the same subjects were acquired in a dedicated small animal PET scanner and transformed to the created MRI template space. To validate these templates for PET quantification, parametric values obtained with a standard VOI-map applied after spatial normalization to each template were statistically compared to results computed using individual VOIs drawn for each animal. The high correlation between both procedures validated the utilization of all the templates, improving the reproducibility of PET analysis. To prove the utility of the templates for voxel-based quantification, dopamine striatal depletion in a representative monkey treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was assessed by SPM analysis of 11 C-DTBZ PET. A symmetric reduction in striatal 11 C-DTBZ uptake was detected in accordance with the induced lesion. In conclusion, templates of M. fascicularis brain have been constructed and validated for reproducible and automated PET quantification. All templates are electronically available via the internet.

Neurobiology of Disease, 2010

Dopaminergic depletion in the nigrostriatal system is the neurochemical hallmark of Parkinson's d... more Dopaminergic depletion in the nigrostriatal system is the neurochemical hallmark of Parkinson's disease (PD). Although numerous efforts have been made to determine the evolution of dopaminergic depletion in PD, "in vivo" data concerning the stages of this process are still scarce. We evaluated 6-[18F]-fluoro-L-DOPA ( 18 F-DOPA) and 11C-(+)-α-dihydrotetrabenazine ( 11 C-DTBZ) using PET in a model of chronically MPTPinduced parkinsonism in non-human primates. Methods: Sixty-seven cynomolgus monkeys (Macaca fascicularis) were included in the study. Progressive parkinsonism was induced by repeated administration of small doses of MPTP (iv) over several months. Animals were classified as controls, asymptomatic, recovered (having exhibited parkinsonian features transiently) and stable parkinsonian, according to their motor status. Analysis of striatal dopaminergic activity was conducted by regions of interest (ROI) and statistical parametric mapping (SPM) over normalized parametric images. Results: A progressive loss of striatal uptake was evident among groups for both radiotracers, which correlated significantly with the clinical motor status. Changes occurred earlier, i.e. in the less affected stages, with 11 C-DTBZ. Similar results were achieved by ROI and SPM analysis. Uptake was similar with both radiotracers for the asymptomatic and recovered groups. Conclusions: Serial assessment with 18 F-DOPA and 11 C-DTBZ PETs provides an effective approach to evaluate evolution of dopaminergic depletion in monkeys with MPTP-induced parkinsonism. This approach could be useful to perform studies aiming to test the effect of early therapeutic intervention and putative neuroprotective treatments.

Movement Disorders, 2010

have to be congratulated for their hypothesis on PD pathogenesis. They suggest that the sequence ... more have to be congratulated for their hypothesis on PD pathogenesis. They suggest that the sequence of the brain changes in PD follows specific and repeatable patterns in all cases, as well as that a prion-like process underlies neurodegeneration. These ideas could explain several features of PD, such as the high prevalence of olfactory, autonomic, or sleep abnormalities. However, any pathogenic hypothesis should also explain:

Journal of the Neurological Sciences, 2010

The diagnosis of Parkinson's disease (PD) is stil... more The diagnosis of Parkinson's disease (PD) is still based on the recognition of the cardinal motor features. However, it is now recognized that non-motor manifestations (NMM) may actually precede the emergence of motor manifestations. NMM are very frequently present in the overall population of PD patients and are a major determinant of their quality of life. In this article we discuss the origin of sensory manifestations in PD, particularly focus on pain mechanisms, which is the most frequent and better studied NMM. Analysis of experimental and clinical data reveals that the basal ganglia (BG) indeed have an anatomo-functional organization which sustains sensory functions. In addition, the dopaminergic system is also engaged in the modulation and integration of sensory information and the response to pain. In patients with PD, pain is often related with motor fluctuations and dyskinesias induced by dopaminergic treatments, which suggest some common mechanisms with the origin of motor complications in PD. Clinically, sensory manifestations are often disturbing and poorly treated and may occasionally become a major cause of disability for PD patients. Thus, more clinical and basic studies are warranted to clarify pain mechanisms in PD, with the aim of achieving better treatments.

European Journal of Nuclear Medicine and Molecular Imaging, 2011

Although specific PET scanners have been developed for small animals, spatial resolution remains ... more Although specific PET scanners have been developed for small animals, spatial resolution remains one of the most critical technical limitations, particularly in the evaluation of the rodent brain. The purpose of the present study was to examine the reliability of voxel-based statistical analysis (SPM) applied to 18 Ffluorodeoxyglucose ( 18 F-FDG) PET images of the rat brain, acquired on a small

Clinical Neuropharmacology, 2005

Quetiapine is an atypical antipsychotic with sedative properties frequently used to treat halluci... more Quetiapine is an atypical antipsychotic with sedative properties frequently used to treat hallucinations and psychosis in Parkinson disease (PD). The objective of this trial is to evaluate quetiapine for insomnia in nonpsychotic PD patients. Fourteen consecutive PD patients with frequent insomnia and without psychotic symptoms were treated openly for 12 weeks with a single evening dose of quetiapine. The dose was adjusted according to clinical improvement and tolerance. The severity of insomnia was assessed using the Pittsburgh Sleep Quality Index (PSQI), daytime sleepiness was evaluated with the Epworth Sleep Scale (ESS), and motor performance was evaluated using the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). All evaluations were done before and 1, 2, and 3 months after initiation of treatment. Total PSQI basal scores were 13.6 6 3.7 points. The PSQI score improved in 11 patients and was reduced by 3.8 6 3.9 points by the end of the study (P , 0.01). The ESS score was reduced by 4.3 6 3.7 points (P , 0.01). The mean quetiapine dose was 31.9 mg/day. No significant change was observed in the motor scale. Two patients were discontinued due to nonserious adverse effects. These results suggest that quetiapine may be a safe and effective treatment of insomnia in PD patients. Doubleblind studies will probably confirm these findings.

Biology of Blood and Marrow Transplantation, 2010

It is thought that the ability of human mesenchymal stem cells (hMSC) to deliver neurotrophic fac... more It is thought that the ability of human mesenchymal stem cells (hMSC) to deliver neurotrophic factors might be potentially useful for the treatment of neurodegenerative disorders. The aim of the present study was to characterize signals and/or molecules that regulate brain-derived neurotrophic factor (BDNF) protein expression/ delivery in hMSC cultures and evaluate the effect of epigenetically generated BDNF-secreting hMSC on the intact and lesioned substantia nigra (SN). We tested 4 different culture media and found that the presence of fetal bovine serum (FBS) decreased the expression of BDNF, whereas exogenous addition of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) to serum-free medium was required to induce BDNF release (125 6 12 pg/day/10 6 cells). These cells were called hM(N)SC. Although the induction medium inhibited the expression of alpha smooth muscle actin (ASMA), an hMSC marker, and increased the nestinpositive subpopulation of hMSC cultures, the ability to express BDNF was restricted to the nestin-negative subpopulation. One week after transplantation into the SN, the human cells integrated into the surrounding tissue, and some showed a dopaminergic phenotype. We also observed the activation of Trk receptors for neurotrophic factors around the implant site, including the BDNF receptor TrkB. When we transplanted these cells into the unilateral lesioned SN induced by striatal injection of 6-hydroxydopamine (6-OHDA), a significant hypertrophy of nigral tyrosine hydroxylase (TH) 1 cells, an increase of striatal TH-staining and stabilization of amphetamine-induced motor symptoms were observed. Therefore, hMSC cultures exposed to the described induction medium might be highly useful as a vehicle for neurotrophic delivery to the brain and specifically are strong candidates for future therapeutic application in Parkinson's disease.

Arquivos de Neuro-Psiquiatria, 2008

Parkinson's disease (PD) is a neurodegenerative disorder, predominantly characterized by the pres... more Parkinson's disease (PD) is a neurodegenerative disorder, predominantly characterized by the presence of motor symptoms. However, the non motor manifestations (NMM) are a frequent complaint in the PD patients. There is a lack of information about the risk factors associated with the NMM in these patients. The aim of this study is to evaluate the prevalence of the more common NMM in a population of PD patients and to determine the features associated with its development. We studied 124 ambulatory PD patients. NMM were defined by the presence of neuropsychiatric manifestations, cognitive disorder, autonomic dysfunction or sleep related problems. In a multivariate analysis we found that the years of evolution of the PD and the presence of cognitive dysfunction are the risk factors for the neuropsychiatric and autonomic manifestations, whereas axial impairment is a risk factor for cognitive disorders and dyskinesias is for sleep related problems.