Browsing by Author "Juri, Carlos"

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    Cerebral metabolic pattern associated with progressive parkinsonism in non-human primates reveals early cortical hypometabolism
    (2022) Molinet-Dronda, Francisco; Blesa, Javier; Lopez-Gonzalez del Rey, Natalia; Juri, Carlos; Collantes, Maria; Pineda-Pardo, Jose A.; Trigo-Damas, Ines; Iglesias, Elena; Hernandez, Ledia F.; Rodriguez-Rojas, Rafael; Gago, Belen; Ecay, Margarita; Prieto, Elena; Garcia-Cabezas, Miguel A.; Cavada, Carmen; Rodriguez-Oroz, Maria C.; Penuelas, Ivan; Obeso, Jose A.
    Dopaminergic denervation in patients with Parkinson's disease is associated with changes in brain metabolism. Cerebral in-vivo mapping of glucose metabolism has been studied in severe stable parkinsonian monkeys, but data on brain metabolic changes in early stages of dopaminergic depletion of this model is lacking. Here, we report cerebral metabolic changes associated with progressive nigrostriatal lesion in the pre-symptomatic and symptomatic stages of the progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's Disease. Monkeys (Macaca fascicularis) received MPTP injections biweekly to induce progressive grades of dopamine depletion. Monkeys were sorted according to motor scale assessments in control, asymptomatic, recovered, mild, and severe parkinsonian groups. Dopaminergic depletion in the striatum and cerebral metabolic patterns across groups were studied in vivo by positron emission tomography (PET) using monoaminergic ([C-11]-dihydrotetrabenazine; C-11-DTBZ) and metabolic (2-[F-18]-fluoro-2-deoxy-D-glucose; F-18-FDG) radiotracers. C-11-DTBZ-PET analysis showed progressive decrease of binding potential values in the striatum of monkeys throughout MPTP administration and the development of parkinsonian signs. F-18-FDG analysis in asymptomatic and recovered animals showed significant hypometabolism in temporal and parietal areas of the cerebral cortex in association with moderate dopaminergic nigrostriatal depletion. Cortical hypometabolism extended to involve a larger area in mild parkinsonian monkeys, which also exhibited hypermetabolism in the globus pallidum pars interna and cerebellum. In severe parkinsonian monkeys, cortical hypometabolism extended further to lateral-frontal cortices and hypermetabolism also ensued in the thalamus and cerebellum. Unbiased histological quantification of neurons in Brodmann's area 7 in the parietal cortex did not reveal neuron loss in parkinsonian monkeys versus controls. Early dopaminergic nigrostriatal depletion is associated with cortical, mainly temporo-parietal hypometabolism unrelated to neuron loss. These findings, together with recent evidence from Parkinson's Disease patients, suggest that early cortical hypometabolism may be associated and driven by subcortical changes that need to be evaluated appropriately. Altogether, these findings could be relevant when potential disease modifying therapies become available.
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    Features associated with the development of non-motor manifestations in Parkinson's disease
    (ASSOC ARQUIVOS NEURO- PSIQUIATRIA, 2008) Juri, Carlos; Viviani, Paola; Chana, Pedro
    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. In conclusion, this study shows that the features related to the PD progression appear as the main risk factors associated with NMM.
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    Intranigral Transplantation of Epigenetically Induced BDNF-Secreting Human Mesenchymal Stem Cells: Implications for Cell-Based Therapies in Parkinson's Disease
    (ELSEVIER SCIENCE INC, 2010) Somoza, Rodrigo; Juri, Carlos; Baes, Mauricio; Wyneken, Ursula; Javier Rubio, Francisco
    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 +/- 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 nestin-positive 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)(+) cells, an increase of striatal TH-staining and stabilization of amphetamine-induced motor symptoms were observed. Therefore, h MSC 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.
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    Pharmacokinetic evaluation of [18F]PR04.MZ for PET/CT imaging and quantification of dopamine transporters in the human brain
    (2020) Kramer, Vasko; Juri, Carlos; Riss, Patrick J.; Pruzzo, Rossana; Soza-Ried, Cristian; Flores, Jonathan; Hurtado, Ana; Roesch, Frank; Chana-Cuevas, Pedro; Amaral, Horacio
    Purpose Dopamine transporters (DAT) modulate pre-synaptic dopamine and physiological functions such as movement and reward. DAT also mirrors disease state in neurological disorders, rendering it an essential diagnostic target. [F-18]PR04.MZ is a new PET imaging agent for DAT with an improved affinity and selectivity profile, for which we here describe the complete pharmacokinetic evaluation in healthy controls. Methods Thirty-two healthy subjects underwent T1-weighted MRI and dynamic PET scans for 180 min with arterial blood sampling (n = 5) or 90 min without blood sampling (n = 25) after injection of 197.6 +/- 12.2 MBq [F-18]PR04.MZ. Blood and plasma metabolite analysis were performed. MRI-based normalization of brain images, delineation of VOIs, and kinetic modeling was conducted to determine distribution volumes (V-t) and binding potentials (BPnd). The impact of scan duration was evaluated and repeated PET scans were performed to assess test-retest variability (n = 5). A static imaging protocol has been validated for clinical applications. Results [F-18]PR04.MZ showed rapid metabolization in circulation, very high uptake in striatum and midbrain, and very low non-specific binding. The two-tissue compartment model 2TCM provided best fits for measured time-activity-curves and calculated V(t)s in putamen, caudate, substantia nigra pars compacta (SNpc), and cerebellar cortex were 11.83, 9.73, 2.12, and 0.57, respectively. All non-invasive models correlated well with BPnd values derived from 2TCM but underestimated DAT availability by about 28-33%. Of those, simplified reference tissue model (SRTM) provided the best fits, lowest Akaike Information Criteria values, and BPnd values of 14.82, 11.95, and 2.63 in putamen, caudate, and SNpc, respectively. BPnd estimates for striatal regions and SNpc were stable between 90 and 130 min post-injection. Test-retest results were excellent, showing low variability in all and excellent reliability in most relevant regions. Static imaging from 60 to 90-min post-injection is a viable alternative for quantification. Conclusions [F-18]PR04.MZ is a PET tracer with very high affinity, selectivity, and specific uptake in striatum and midbrain. 2TCM and SRTM provide good fits, high and stable V(t)s or BP(nd)s, and good test-retest reliability for precise quantification of DAT in human subjects.
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    Prodromal manifestations of Parkinson’s disease in adults with 22q11.2 microdeletion syndrome
    (2022) Juri, Carlos; Chaná-Cuevas, Pedro; Kramer, Vasko; Fritsch, Rosemarie; Ornstein, Claudia; Cuiza, Analía; Hernández, Carlos; Villanueva, Katiuska; Cordova, Teresa; Mauro, Jorge; Ocampo, Adrián; Rebolledo-Jaramillo, Boris; Repetto, Gabriela M.
    22q11.2 microdeletion syndrome (22qDS) was recently identified as a risk factor for development of early-onset Parkinson´s disease (PD). The classical motor manifestations of this disease are preceded by early signs and symptoms of neurodegeneration. The progression of 22qDS-associated PD is unknown. We aimed to evaluate the presence of prodromal PD in a group of adults with 22qDS using the Movement Disorders Society (MDS) Criteria for Prodromal PD. Thirty-eight persons with 22qDS and 13 age-matched controls participated in the study, and their results were compared using the MannWhitney U test. Persons with 22qDS had lower scores on olfaction testing (p=7.42Ex10-5), higher scores on the COMPASS 31 scale for dysautonomia (p=2.28x10-3) and on the motor evaluation using Movement Disorder Society (MDS)-sponsored revision of Unified Parkinson’s Disease Rating Scale motor subscore (UPDRS-III) (p=1.84x10-4), compared with healthy controls. Home polysomnogram did not find participants with REM-sleep behavior disorder. Integrity of nigrostriatal dopaminergic system was evaluated by PET-CT imaging of presynaptic dopamine with 18F-PR04.MZ. Patients showed significantly higher specific binding ratios in the striatum, compared to controls (p=9.57x10-3 at the caudate nuclei). Two patients with 22qDS (5.2%) had decreased uptake in the posterior putamen (less than 60% of controls) and one fulfilled MDS criteria for prodromal PD. These results show that patients with 22qDS manifest some signs and symptoms of prodromal PD such as hyposmia, dysautonomia and mild movement alterations. In the majority, this was associated with elevated dopaminergic signaling, suggesting that loss of dopaminergic neurons may not be the cause. A smaller subgroup did show evidence of a decrease in nigrostriatal dopaminergic signaling, as seen in classical prodromal PD. Longitudinal studies are necessary to understand the progression to and risk of PD in persons with 22qDS.
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    Progression of dopaminergic depletion in a model of MPTP-induced Parkinsonism in non-human primates. An F-18-DOPA and C-11-DTBZ PET study
    (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2010) Blesa, Javier; Juri, Carlos; Collantes, Maria; Penuelas, Ivan; Prieto, Elena; Iglesias, Elena; Marti Climent, Josep; Arbizu, Javier; Zubieta, Jose L.; Cruz Rodriguez Oroz, Mari; Garcia Garcia, David; Richter, Jose A.; Cavada, Carmen; Obeso, Jose A.
    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 (F-18-DOPA) and 11C-(+)-alpha-dihydrotetrabenazine (C-11-DTBZ) using PET in a model of chronically MFTP-induced 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 C-11-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 F-18-DOPA and C-11-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. (C) 2010 Elsevier Inc. All rights reserved.
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    Statistical parametric maps of 18F-FDG PET and 3-D autoradiography in the rat brain: a cross-validation study
    (2011) Prieto, Elena; Collantes, Maria; Delgado, Mercedes; Juri, Carlos; Garcia-Garcia, Luis; Molinet, Francisco; Fernandez-Valle, Maria E.; Pozo, Miguel A.; Gago, Belen; Marti-Climent, Josep M.; Obeso, Jose A.; Penuelas, Ivan
    Purpose Although specific positron emission tomography (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 (Statistical Parametric Mapping, SPM) applied to F-18-fluorodeoxyglucose (FDG) PET images of the rat brain, acquired on a small animal PET not specifically designed for rodents. The gold standard for the validation of the PET results was the autoradiography of the same animals acquired under the same physiological conditions, reconstructed as a 3-D volume and analysed using SPM.
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    [18F]PR04.MZ PET/CT Imaging for Evaluation of Nigrostriatal Neuron Integrity in Patients With Parkinson Disease
    (2021) Juri, Carlos; Kramer, Vasko; Riss, Patrick J.; Soza-Ried, Cristian; Haeger, Arlette; Pruzzo, Rossana; Rosch, Frank; Amaral, Horacio; Chana-Cuevas, Pedro
    Introduction