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Cerebral metabolic pattern associated with progressive parkinsonism in non-human primates reveals early cortical hypometabolism.

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2022-06-01

Authors

Molinet-Dronda, Francisco
Blesa, Javier
López-González-Del-Rey, Natalia
Juri, Carlos
Collantes, Maria
Pineda-Pardo, Jose A
Trigo-Damas, Ines
Iglesias, Elena
Hernandez, Ledia F
Rodriguez-Rojas, Rafael

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Academic Press
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Abstract

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 ([11C]-dihydrotetrabenazine; 11C-DTBZ) and metabolic (2-[18F]-fluoro-2-deoxy-d-glucose; 18F-FDG) radiotracers. 11C-DTBZ-PET analysis showed progressive decrease of binding potential values in the striatum of monkeys throughout MPTP administration and the development of parkinsonian signs. 18F-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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MeSH Terms

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Animals
Cerebral Cortex
Corpus Striatum
Dopamine
Humans
Parkinsonian Disorders
Positron-Emission Tomography
Primates

DeCS Terms

Globo pálido
Enfermedad de Parkinson
Neuronas
Fluorodesoxiglucosa F18
Macaca fascicularis
Corteza cerebral
Fluorodesoxiglucosa F18
Dopamina
Tálamo
Metabolismo
Desoxiglucosa

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Keywords

Glucose metabolism, Parkinson's disease, Positron emission tomography (PET), [(11)C]-dihydrotetrabenazine ((11)C-DTBZ), [(18)F]-fluoro-2-deoxy-d-glucose ((18)F-FDG)

Citation

Molinet-Dronda F, Blesa J, Del Rey NL, Juri C, Collantes M, Pineda-Pardo JA, et al. Cerebral metabolic pattern associated with progressive parkinsonism in non-human primates reveals early cortical hypometabolism. Neurobiol Dis. 2022 Jun 1;167:105669.