Dataset Information

Induced Cognitive Impairments Reversed by Grafts of Neural Precursors: A Longitudinal Study in a Macaque Model of Parkinson's Disease.

ABSTRACT: Parkinson's disease (PD) evolves over an extended and variable period in humans; years prior to the onset of classical motor symptoms, sleep and biological rhythm disorders develop, significantly impacting the quality-of-life of patients. Circadian-rhythm disorders are accompanied by mild cognitive deficits that progressively worsen with disease progression and can constitute a severe burden for patients at later stages. The gold-standard 6-methyl-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) macaque model of PD recapitulates the progression of motor and nonmotor symptoms over contracted periods of time. Here, this multidisciplinary/multiparametric study follows, in five animals, the steady progression of motor and nonmotor symptoms and describes their reversal following grafts of neural precursors in diverse functional domains of the basal ganglia. Results show unprecedented recovery from cognitive symptoms in addition to a strong clinical motor recuperation. Both motor and cognitive recovery and partial circadian rhythm recovery correlate with the degree of graft integration, and in a subset of animals, with in vivo levels of striatal dopaminergic innervation and function. The present study provides empirical evidence that integration of neural precursors following transplantation efficiently restores function at multiple levels in parkinsonian nonhuman primates and, given interindividuality of disease progression and recovery, underlines the importance of longitudinal multidisciplinary assessments in view of clinical translation.

SUBMITTER: Wianny F

PROVIDER: S-EPMC8981458 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Induced Cognitive Impairments Reversed by Grafts of Neural Precursors: A Longitudinal Study in a Macaque Model of Parkinson's Disease.

Wianny Florence F Dzahini Kwamivi K Fifel Karim K Wilson Charles Robert Eden CRE Bernat Agnieszka A Dolmazon Virginie V Misery Pierre P Lamy Camille C Giroud Pascale P Cooper Howard Michael HM Knoblauch Kenneth K Procyk Emmanuel E Kennedy Henry H Savatier Pierre P Dehay Colette C Vezoli Julien J

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20220209 10

Parkinson's disease (PD) evolves over an extended and variable period in humans; years prior to the onset of classical motor symptoms, sleep and biological rhythm disorders develop, significantly impacting the quality-of-life of patients. Circadian-rhythm disorders are accompanied by mild cognitive deficits that progressively worsen with disease progression and can constitute a severe burden for patients at later stages. The gold-standard 6-methyl-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPT ...[more]

PMID: 35137562

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Project description:BackgroundCognitive decline occurs frequently in Parkinson's disease (PD), which greatly decreases the quality of life of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by overactivated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using a rotenone-induced mouse PD model.MethodsTo evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by Morris water maze, objective recognition, and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation, and apoptosis were determined by immunohistochemistry and Western blot or immunofluorescence staining. The gene expression of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively.ResultsRotenone dose-dependently induced cognitive deficits in mice by showing decreased performance of rotenone-treated mice in the novel objective recognition, passive avoidance, and Morris water maze compared with that of vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, and Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. A time course experiment revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 and minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in mice treated with combined PLX3397 or minocycline and rotenonee compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis.ConclusionsTaken together, our findings suggested that microglial activation contributes to cognitive impairments in a rotenone-induced mouse PD model via neuroinflammation, oxidative stress, and apoptosis, providing novel insight into the immunopathogensis of cognitive deficits in PD.

Project description:In order to gain a better understanding of aphasia one must consider the complex combinations of language impairments along with the pattern of paraphasias. Despite the fact that both deficits and paraphasias feature in diagnostic criteria, most research has focused only on the lesion correlates of language deficits, with minimal attention on the pattern of patients' paraphasias. In this study, we used a data-driven approach (principal component analysis - PCA) to fuse patient impairments and their pattern of errors into one unified model of chronic post-stroke aphasia. This model was subsequently mapped onto the patients' lesion profiles to generate the triangulation of language-cognitive impairments, naming errors and their neural correlates. Specifically, we established the pattern of co-occurrence between fifteen error types, which avoids focussing on a subset of errors or the use of experimenter-derived methods to combine across error types. We obtained five principal components underlying the patients' errors: omission errors; semantically-related responses; phonologically-related responses; dysfluent responses; and a combination of circumlocutions with mixed errors. In the second step, we aligned these paraphasia-related principal components with the patients' performance on a detailed language and cognitive assessment battery, utilising an additional PCA. This omnibus PCA revealed seven unique fused impairment-paraphasia factors: output phonology; semantics; phonological working memory; speech quanta; executive-cognitive skill; phonological (input) discrimination; and the production of circumlocution errors. In doing so we were able to resolve the complex relationships between error types and impairments. Some are relatively straightforward: circumlocution errors formed their own independent factor; there was a one-to-one mapping for phonological errors with expressive phonological abilities and for dysfluent errors with speech fluency. In contrast, omission-type errors loaded across both semantic and phonological working memory factors, whilst semantically-related errors had the most complex relationship by loading across four factors (phonological ability, speech quanta, executive-cognitive skills and circumlocution-type errors). Three components had unique lesion correlates: phonological working memory with the primary auditory region; semantics with the anterior temporal region; and fluency with the pre-central gyrus, converging with existing literature. In conclusion, the data-driven approach allowed derivation of the triangulation of deficits, error types and lesion correlates in post-stroke aphasia.

Dataset Information

Induced Cognitive Impairments Reversed by Grafts of Neural Precursors: A Longitudinal Study in a Macaque Model of Parkinson's Disease.

Publications

Induced Cognitive Impairments Reversed by Grafts of Neural Precursors: A Longitudinal Study in a Macaque Model of Parkinson's Disease.

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