Parkinson's Disease Model
Parkinson's disease (PD) is a complex, multi-system neurodegenerative disorder and is the second most common neurodegenerative disorder worldwide. The global prevalence of PD is conservatively estimated at 0.3%, with the incidence increasing 5-10 times in individuals over the age of 60. Genetic causes or genetic risk variants explain 16-36% of PD cases, while other causes include environmental factors and interactions between genetic and environmental factors.
The hallmark symptoms of PD are motor symptoms, such as bradykinesia combined with either rest tremor, rigidity, or both. Additionally, non-motor symptoms like cognitive decline and sleep disturbances are also prevalent. The pathophysiology of PD involves several mechanisms, including aberrant α-synuclein aggregation, dysfunction of mitochondria, lysosomes or vesicle transport, synaptic transport issues, and neuroinflammation. These mechanisms collectively result in accelerated neuronal death, primarily affecting dopaminergic neurons, and cause circuit dysfunction.
Advantages of NHP disease model
NHP PD models, currently based on neurotoxicity or virus vector-mediated PD pathology, typically induce PD symptoms and behaviors similar to humans. They offer key advantages due to NHP evolutionary similarity to humans in size, behavior, physiology, biochemistry, immune function, and brain structure. Commonly used NHPs, such as macaques, exhibit learning, cognition, emotional, and social abilities, making them suitable for studying both motor and non-motor PD symptoms compared to rodents and pigs. The high similarity between NHP and human brains allows for non-invasive, high-resolution imaging techniques such as MRI and PET. NHP PD models provide valuable insights into PD pathology and are crucial for preclinical drug trials, bridging the gap between basic research and human clinical studies.
Study design and clinical endpoints
•Time-efficient, requiring only a single injection
•Symptoms are stable, with less individual variation
•Eliminate systemic non-PD toxicity
•MPTP is neurotoxic; animals need isolation during early modeling
•Repeated injections are necessary to prevent spontaneous recovery
•Clinical Rating: Kurlan's Scale
•Behavioral analysis: AI-based 3D Behavior Analysis
•Fine motor skill test: Brinkman board test, Object retrieval task
•Muscle strength grading
•Imaging: 11C-CFT PET-CT, MRI
•Pathophysiology: Tyrosine Hydroxylase immunoreactivity (TH-ir; a dopaminergic neuronal marker)
•Sleep-wake cycles
•Locomotor activity
•Drug-induced rotation response
•Classic positive drug treatment: L-DOPA
•Cognition test: DMTS task
•Neurochemical analysis: HPLC for DA and its metabolites
key result and figure legend
AI-based 3D Behavior Analysis of 1-hour video segments at different time points for 3 animals. PD modeling show reduced gross motor frequency (e.g., climbing, falling) and head movements frequency (e.g. rising, lowering) compared to baseline (grey shading)
Quantitative analysis results of SUVR of striatal dopamine transporter (DAT) radioactive uptake for ipsilateral (orange) and contralateral (blue) hemisphere at different time points using 11C-CFT PET-CT. Representative uptake images in baseline and PD modeling.
Contact time for each slots in Brinkman board test at different time points for contralateral hand (blue) and the ipsilateral hand (orange). The statistical comparisons between the two hands in each session were performed using the nonparametric Mann-Whitney test. Mean±SEM. n.s, not significant,***p<0.001.
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