The PD-AGE international task force (https://www.sheffield.ac.uk/pd-age) focuses on advancing our understanding of the role of ageing in Parkinson’s disease (PD). Our mission was to identify the most effective models and methodologies for studying the impact of ageing on PD. Among the multiple models used, PD research is characterised by a unique, repeatedly proven, bench-to-bedside translational role played by non-human primate (NHP) models in developing new therapeutic modalities, as NHPs offer valuable insights that other models cannot fully capture1, 2, 3, 4, 5–6. The perfect illustration of the use of these NHP studies is the definition of basal ganglia circuitry7, 8, 9, 10–11, soon followed by the demonstration that lesioning the subthalamic nucleus alleviated PD-like cardinal symptoms in NHPs with parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)6,12. This seminal work led to the discovery of the profound symptomatic relief afforded by subthalamic nucleus deep brain stimulation in MPTP NHPs13, followed a few months later by PD patients14,15, a procedure giving life-altering benefits to hundreds of thousands of PD sufferers. This advance could only be established thanks to NHPs.
Inspired by these previous breakthroughs, the PD-AGE NHP-focused working group was tasked to explore the role of NHPs in advancing our understanding of PD and ageing to provide a roadmap for generating the necessary knowledge, resources, and tools.
Importance of non-human primate models of PD and ageing
NHPs are closely related to humans. Depending on the species, they share 93–96% of the DNA sequence identity with humans, compared to rodents, which is limited to 85% homology. Rhesus and cynomolgus macaques and common marmoset monkeys are the NHP species most often used in biomedical research (most likely because of abundant availability from breeding facilities), followed by African green monkeys, baboons, and squirrel monkeys16. This high sequence similarity results in similar brain anatomy and behaviour, especially for the prefrontal cortex, hippocampus, basal ganglia, and substantia nigra17, 18–19. Indeed, the limited development of the prefrontal cortex in rodents20 makes the use of mice, transgenic or otherwise, very problematic for studying human diseases that affect this region, such as PD.
PD is characterised by the degeneration of dopaminergic neurons in the substantia nigra21 and the presence of Lewy pathology across the entire nervous system. Since monkeys exhibit a neuroanatomy and physiology comparable to humans, they can be used to model complex neurological disorders such as PD more effectively than rodents, which have very different brains in terms of size, organisation, number of connections, proportion of glia to neurons, presence or absence of neuromelanin in substantia nigra dopaminergic neurons, among others traits4,21. The high anatomical and functional correspondence between NHPs and humans yields information not obtained from rodent models. For instance, NHPs exhibit a full spectrum of human-like higher-order cognitive behaviours, including problem-solving, decision-making, social interactions, and emotional responses22. Given that PD is not only a motor disorder in humans but also affects cognition, mood, and social behaviour, the large behavioural repertoire of NHPs is essential for investigating non-motor features of PD and ageing with the same tools/opposite endpoints used in the clinic or human psychology. This makes NHPs essential for understanding the ageing-associated diseases that affect not only the physical state but also the cognitive and emotional status23.
Despite monkeys having a longer life span than rodents (20–40 years, depending on the NHP species, vs ~2 years in rodents), it is significantly shorter than the human lifespan, yet it still shows age-related changes reminiscent of human ageing. Numerous disorders and conditions of ageing can be modelled faithfully in NHP, including sarcopenia, osteoporosis, arthritis, age-related cancers, and diabetes24. Furthermore, primates age and develop prodromal age-related brain pathology reminiscent of what is seen in aged humans that may lead to prodromal AD and PD, providing a valuable perspective on disease aetiology3,25. Female macaques display reproductive senescence around 15–20 years, with menopause reported around 23 years of age26; rhesus may develop mild cognitive impairment by age 20. Common marmosets do not undergo reproductive senescence but are considered aged when they reach 8 years27. The accumulation of neuromelanin in the dopaminergic neurons of the substantia nigra in aged NHPs is comparable to that in humans, and the age-related loss of tyrosine hydroxylase-positive neurons is a feature of PD28,29. Interestingly, the naturally occurring ageing-related pathology in NHPs includes dopaminergic neuron loss30, robust amyloid beta plaque formation, and, in a few cases, phosphorylated tau aggregation in a pattern comparable to the one seen in humans31. This allows for better capture of the onset and progression of neurodegenerative diseases and their relationship with ageing, making NHPs a valuable model for studying pathological and behavioural changes associated with normal ageing and ageing-related diseases.
The ability to do long-term, longitudinal studies on NHPs is a considerable advantage over the short-term cross-sectional studies done in rodents. First, the longer life of NHPs enables the researchers to study the impact of ageing on neurodegenerative diseases, which is especially helpful in understanding the effects of age-related changes that may be challenging to capture in shorter-lived animals. Moreover, neurodegenerative diseases like PD are chronic, and understanding the dynamics of the disease progression is key to identifying early biomarkers, studying the disease pathophysiology, and assessing candidate treatment efficacy. NHPs enable the testing of the same subjects over many years, allowing for the observation of the gradual appearance of symptoms, neurodegeneration, and cognitive deterioration. These unique features of NHPs are essential to study the progression and determine how interventions may change or even slow down the course of PD motor and non-motor symptoms. Lastly, the commonly used unilateral 6-OHDA-treated rodent model of PD only displays unilateral abnormal involuntary movements and usually requires amphetamine for their manifestation32. In contrast, it is generally recognised that the bilateral macaque model of levodopa-induced dyskinesias is the most optimal animal model for this often debilitating side effect that occurs in >80% of individuals with PD33.
In summary, NHP models provide a uniquely powerful tool for studying PD and ageing due to their close genetic, anatomical, and neurological similarities to humans, ability to demonstrate complex behaviours and cognition, long lifespan, and natural ageing process that mirrors human disease progression34. Longitudinal studies in NHPs offer insights that are difficult, if not impossible, to replicate in rodents, making them indispensable for advancing our understanding of neurodegenerative diseases and the development of effective treatments.
Challenges and ethical considerations
Using NHPs in research raises important ethical issues, especially concerning animal welfare. Ethical frameworks must guarantee that the scientific and translational advantages of NHP studies are not a threat to animal welfare. Such frameworks always entail passing ethical review processes and ongoing oversight by Institutional Animal Care and Use Committees (IACUCs, or similar, depending on the country) and following guidelines such as the 3Rs (Replacement, Reduction, and Refinement). Establishing collectively agreed transnational standards of housing and care, transparent protocols for minimum suffering, and humane endpoints are also key measures that help address ethical concerns and enforce frameworks. One point that merits additional clarification is that the term ‘reduction’ does not simply refer to reducing the number of animals used. It means reducing the number while still ensuring that the hypothesis can be tested adequately, as underpowering a study is a poor use of animals that leads to inconclusive results. It is also important to use unbiased, blinded evaluation methods and adhere to ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments)35 for reporting NHP research.
Longitudinal NHP studies are costly and resource-intensive, requiring specific facilities with strict health and welfare standards and the expertise of many people to provide effective and comprehensive care of the animals, monitor them, implement protocols, and acquire and analyse the data. In addition, the long life of NHPs makes it challenging to carry out longitudinal studies as they need lengthy observation and management. Incorporating additional complicated functional and biological information (e.g., genetic, neuroimaging, behaviour, and post-mortem assessments) increases both the cost and difficulty. Thus, to make the most of NHP research and address these challenges, the allocation of resources and funding must be well thought out. An international research consortium would aid in overcoming financial limitations by allowing collaboration to share costs and data, thereby reducing the overall number of NHPs. This consortium could help with cross-sectional and longitudinal studies by combining resources and ensuring that geography or finance does not hinder advancing research or ethical standards. A good example of such a joint effort has recently been published by international investigators using optogenetic approaches in NHPs36. Developing a coordinated plan to centralise in vivo experiments, combined with many visiting international labs/investigators performing in-life data collection and distributed post-mortem analyses, would increase the feasibility and effectiveness of NHP research. This collaborative international infrastructure would also assist in simplifying data integration and enhancing the precision and accuracy of the results of various studies. Finally, this effort would not only address some of the ethical concerns around the involvement of NHPs in research protocols in terms of public opinion, but importantly it would greatly contribute to reassure the researchers, technicians and caretakers working in the field that selected precious experiments conducted on this species can yield a wealth of robust and predictive data that has a direct impact on increasing knowledge and clinical developments in the diagnosis, follow-up and treatment of patients.
Improvements needed in models, tools, and outcomes
There is a need for better, standardised NHP models of PD and ageing that are more similar to the actual human disease and disease progression1,2. Spontaneous neuropathology in NHP does not encompass all of the specific pathological characteristics of PD observed in human patients, including progressive α-synuclein aggregation and neurodegeneration (a difference from tau). It is possible to recreate those pathologies through interventions that can be matched to the specific research question. For example, many studies have used transgenic/genetic models37,38, inoculation of patient-derived aggregated protein extracts39, 40–41 or recombinant α-synuclein pre-formed fibrils (PFFs)42, 43, 44, 45–46, toxin-based47, 48, 49, 50–51, and viral vector-mediated approaches52,53 to address specific elements in the disease trajectory and treatment response. One should, however, be mindful that the choice of the most appropriate model to be used largely relies on the scientific questions being asked. Having an NHP model for a complex disease like PD cannot, at present, be envisioned, especially as PD presentation varies across patients. By combining different approaches, there is room for improvement in inducing specific aspects of the disease that can bring us closer to the human condition.
Although many tools are already available for assessing motor and non-motor functions in NHPs (e.g. ref. 54), many have not been thoroughly compared or are less consistently employed than human clinical tools. For example, other than human-like clinical scales for various symptoms, clinically relevant assessments such as wearable sensors, deep learning motion capture analysis, and touchscreen-based cognitive testing should be further back-validated in NHPs to increase their translational value. Few laboratories have been able to capture normal cognitive decline due to ageing, and by creating a database, these endeavours could benefit a larger community of scientists working on PD models to tease out specific contributions and refine the evaluation of therapeutic strategies.
Similarly, there is a need to develop comprehensive biomarkers and imaging technologies for early-stage PD and ageing in NHPs (e.g. 55, 56–57). They are extremely valuable, as many of the confounding variables in human studies (environment, lifestyle, diet, physical activity) can be controlled for in NHP studies. To track disease progression, longitudinal imaging should be investigated using PET and MRI in NHPs to document the state of the dopaminergic system, glucose consumption, synaptic changes, cerebral blood flow, glutamate content, iron signatures, and functional networks, amongst other biomarkers. Furthermore, the development of validated blood and CSF assays for α-synuclein (total, oligomeric, fibrillar, with attention to the different polymorphs and post-translational modifications), neurofilament light chain, tau (in various forms), and inflammatory cytokines is needed for their evaluation as potential biomarkers of neurodegeneration and inflammation.
The post-mortem endpoints are numerous, and the number keeps increasing. A minimal standard of required information needs to be defined together with agreed protocols, down to specific tissue preparation and handling for further exploitation through techniques ranging from omics to immunohistological pathological examinations, antibody selection, exact procedures for staining, virtualisation of stained sections for sharing of technical soundness and analysis methodologies, as well as distributing the analysis workload.
Finally, we found a lack of optimisation in platforms dedicated to the preclinical testing of therapies for PD and age-related neurodegenerative conditions that are confined to a few research centres with limited collaboration. Such a situation hampers translational efforts and, considering the above-mentioned costs, represents an opportunity for a consortium to shape future directions. NHPs are a superior translational model for human ageing and human conditions, where biological insights, treatment efficacy, and clinical endpoints are likely highly conserved. As such, an international consortium to share standardised protocols, model validation data, and therapeutic screening platforms would accelerate drug discovery and translational research.
Recommendations
Develop Improved NHP Models
Most of our current knowledge of PD and ageing is from old-world macaque monkey studies, but many pharmacological studies have also been carried out in New World marmoset monkeys. These two species should remain the species of choice, building upon their assets. The marmoset monkeys have the benefit of being smaller in size and having a relatively short life span, giving the possibility of establishing closed colonies within individual institutions and Japan-sponsored efforts towards creating genetically engineered marmosets. Bred F2 macaque monkeys are widely available in large quantities, with the limitations (i) of geopolitical decisions (the People’s Republic of China temporarily banned Rhesus macaque export in the post-COVID period, disrupting access to this valuable species for some time) and (ii) transportation issues from production areas to research labs. Although longitudinal studies may be complex because of their life span, cross-sectional studies are feasible, given proper investment, building on the current knowledge of PD and ageing, which has been contributed to by the authors, among others.
The MPTP model is the most standardised NHP model of PD with excellent phenotypic similarity to human symptoms. Indeed, MPTP-treated NHPs can mimic PD cardinal motor symptoms, gait disorders, and other non-motor symptoms such as wake-cycle disturbances and cognitive issues, as well as the side effects of dopamine-replacement therapy. MPTP intoxication remains the only NHP model that can cause a comprehensive loss of nigrostriatal dopamine and best mimic key features of the pathophysiology of the basal ganglia–thalamocortical circuits described in human parkinsonism1,58. However, the mechanism of degeneration is quite different between MPTP toxicity and human PD, so the use of this model depends on the specific question being asked.
Several alternative models are available, but very few are shared between laboratories and thus require protocol standardisation to induce PD-like degeneration. Some examples include intracerebral viral vector-mediated synuclein overexpression or up/down-regulation of PD-related genes (Parkin, DJ-1, ATP13A2, etc.), seeding models induced by PD patient-derived brain homogenates or α-synuclein PFFs, and transgenic or genome-edited PD models by embryonic or germline modification59 (People’s Republic of China in particular launched a heavily-funded transgenic macaque programme60). The latest developments using AAV-mediated overexpression of tyrosinase in dopaminergic mesencephalic neurons have the potential, together with seeding insults, to mimic age-related PD-like models52. Direct comparisons among these highly promising models can potentially advance the field significantly. Such complex validation could not be undertaken by any individual investigator but could be accomplished by a consortium of dedicated scientists.
Enhance NHP-specific tools and methodologies
The investigation of PD and ageing in NHPs is an emerging field that requires ongoing innovation and enhancement of techniques to evaluate disease progression and neurobehavioral alterations. As the disease manifests with multiple symptoms and the ageing process is accompanied by complex neurological changes, it is crucial to innovate and improve the current tools and create new methods suitable for research with NHPs that are pertinent for the clinic.
One critical area for development is enhancing the behavioural assays to capture the diverse manifestations of motor and non-motor dysfunction in PD and ageing. Current methods of assessing movement disorders in NHPs include basic tests of the reach-to-grasp type and the application of various Neurology-like scales. Inspired by the clinical experience, where subjectiveness in scoring movement disorders has hampered cross-comparisons between clinical trials, this consortium could provide the community with a video-based training platform that allows for standardisation of methods. Liaising with neurologists, it could highlight the most clinically relevant features compared to PD patient scales and, for example, define an integrated z-score of disability. Building on this effort, these “classic” assessments could be combined with more sensitive methods, including automated wearable or AI-video-based behavioural monitoring and/or kinematic tracking systems to identify even subtle deficits. In that regard, a consortium can facilitate the development of an extensive library of validated data, such as videos previously coded by reliable investigators, which is needed for the successful application of machine learning approaches. Also, the evaluations should be widened to include other aspects of the disease besides motor symptoms, such as sleep problems, smell impairment, mood, memory, cognitive impairment, and autonomic dysfunction, which are now recognised as important, often present as prodromal features of the disease. Indeed, cognitive decline is one of two symptoms of PD (the other being falls) that lead PD patients to opt for nursing home care. As 80% of PD patients have cognitive impairments that can lead to dementia, this particular non-motor feature of PD needs to be specifically and urgently addressed. The tests on cognitive and social interaction should also be improved to give a better understanding of the changes that occur with ageing. This could be achieved by standardising a battery of touchscreen-based tasks that include attention, working memory, executive function, social recognition, perseverative behaviours, and apathy, and hence be able to monitor the rate of cognitive decline61,62. Furthermore, social behaviour assays such as the naturalistic group interactions and social decision-making tasks may help to understand how PD/ageing impacts social cognition and group dynamics.
Concurrently, the application of non-invasive neuroimaging techniques, such as PET and MRI, is crucial for assessing disease dynamics and neurodegeneration in the living subject. Improved spatial resolution in imaging techniques, functional MRI methodologies including fMRI, CEST, and spectroscopy, as well as new PET tracers to investigate α-synuclein accumulation and neuroinflammation, will allow longitudinal analysis of neurobiological changes at the morphological and physiological levels, which could be correlated with CSF and blood biomarkers. Recent advancements in AI suggest that, by combining PET/MRI and histopathological data in discovery cohorts, it should be possible to use MRI for detecting early dysfunctions not yet even dreamt of by the community63 and, thus, to use MRI biomarkers for assessing potential treatments. Combining these data with single-nucleus RNASeq and spatial transcriptomic/proteomic techniques would also benefit from a central repository.
Such advancements go with the necessary development of guidelines for reporting the development of NHP PD models, as has been done for reporting practices for publishing Results with Human Pluripotent and Tissue Stem Cells and ARRIVE. Publication in open-access journals with full disclosure of all raw data deposited on available public repositories, and ideally in an NHP PD community website.
Therefore, improving the motor and cognitive behavioural, ethological and neuroimaging methodologies specific for NHP research will significantly increase the translational value of the preclinical models of PD and ageing, provided we obtain them in a reporting quality framework. The developments will eventually help to improve the understanding of the pathogenic processes underlying neurodegeneration and ageing and inform the development of better treatment approaches or more sensitive outcome measures that are translatable to the clinic.
Increase collaborative research
To improve the current knowledge on PD and ageing in NHPs, it is crucial to enhance the cooperation between neuroscience, neuropsychology, ageing studies, and biomedical engineering. Combining technical expertise from these fields and improving the rigour and sensitivity of the tools, methods, and analyses to simulate the human-diseased conditions more accurately will increase the translational value of NHP PD models for the search for biomarkers and more efficient antiparkinsonian treatment approaches. Another essential step will be the creation of an international research consortium that will investigate PD and ageing in NHPs. This would allow for shared data, methodologies, and technological advancements, thus increasing the significance of the scientific discoveries. Most importantly, this repository should be used to store all results, including negative outcomes, to avoid repeating inconclusive or failed experiments and therefore prevent the misuse of NHPs36,64. Establishing a centralised website representing the consortium that would house information about resources, including guidelines, protocols, results, and available materials/tissues, will be a central deliverable.
We suggest a collaborative framework of a network of live-phase laboratories for in vivo studies for behavioural assessment, imaging, and satellite units for biomarkers, and many post-mortem analyses. This type of research model would allow for a more standardised and detailed analysis of the disease course, neuropathological changes, and treatment effects while increasing the credibility of the studies.
Funding and resources allocation
The need to find appropriate cures for PD cannot be overemphasised. Because NHP studies are costly and require unique facilities, it is vital to establish funding mechanisms that can sustain the availability of these resources for both academic institutions and biotechnology companies. Long-term funding from governments, private foundations, and industry partners will be crucial for the sustainability of the research, continuity, and innovation, leading to the translation of preclinical findings into clinical practice. Strategic investment leading to hundreds of millions of dollars has expanded and advanced Chinese NHP research, placing it in a leading role globally. Another important recommendation is establishing specific grant opportunities for NHP research through multi-centre and interdisciplinary applications. The seven NIH-supported National Primate Centres in the United States bear a broad portfolio of research disciplines, and their expertise could be leveraged to help in this endeavour. Still, it should certainly be accompanied by other European-driven initiatives.
Establishing new grant opportunities for NHP research will encourage investigators to incorporate NHP models of PD and ageing in their studies, thus enhancing the field’s breadth of knowledge. Moreover, cooperation between the public and private sectors can help to share resources and develop new technologies, such as new ways of assessing behaviour and imaging the brain, that would be useful for both academia and industry. Apart from the financial support of the research projects, educating the next generation of scientists in the NHP research field is equally important and requires investment. Establishing structured international training programmes, including fellowships, practical courses, and inter-disciplinary exchange programmes, will help new investigators learn how to conduct research with NHPs effectively. It is crucial for such programmes to focus on ethical aspects of the research, methods, and translation to highlight the future generation of researchers who will be conducting high-quality and ethical research that contributes to scientific development.
A guarantee of funding and development of early-stage research personnel will ensure the further development of the NHP research in the context of ageing and neurodegenerative diseases. These efforts will enhance the scientific infrastructure vital for developing translationally positioned therapeutic strategies to improve patients’ quality of life with neurodegenerative diseases.
Roadmap for generating knowledge, resources, and tools
We propose a 3-step roadmap with clear milestones and deliverables.
Phase 1: Foundation and infrastructure (0–2 years)
We propose establishing an interdisciplinary research consortium, the core represented by this paper’s international authorship, to define key research priorities and methodologies. Most of the work will be devoted to establishing consensual methodologies and implementing regular revisions. This consortium aims to establish international research laboratories to pool knowledge, expertise, and resources, with full access to consortium members near a primate research centre and/or AAALAC-accredited breeding facility with imaging capabilities and several post-mortem labs.
In parallel, while setting up the laboratories, we would develop centralised biorepositories of healthy aged and PD-like NHP tissue and fluid samples (with the community’s various modelling paradigms), imaging data, genetic information, and behavioural data. We would devise and implement data and tissue acquisition procedures and design request application tools to ensure broad participation from colleagues and peers internationally and grant accessibility to the scientific community at large. Finally, we would initiate a global ethical review body for NHP research in neurodegenerative diseases, whose mission will be to provide guidelines and standards to all NHP researchers worldwide.
Phase 2: Development of advanced models (1–4 years)
In the purposedly established facilities, we will design and implement existing and new models of PD and ageing in NHPs with translational relevance to human PD and ageing. We will develop a robust platform (the live phase labs) for cross-sectional & longitudinal studies, including comprehensive motoric, cognitive, and ethological assessments, with, necessarily, an imaging capacity nearby. We will build advanced, non-invasive monitoring tools (e.g. wearables and/or imaging, biomarkers) for real-time model/degeneration/proteinopathy/“disease” progression analysis.
Phase 3: Implementation and scaling (5+ years)
Pending consortium in-depth review and recommendation, we will scale successful research models and methodologies for grounding accelerated translational efforts towards selecting consensually defined disease-modifying strategies. We will expand international collaborations for broad application and knowledge-sharing. We will disseminate best practices for the ethical, scientific, and technological aspects of NHP use in ageing and PD research.
Conclusion
We here advocate that NHPs are essential for advancing our understanding of PD and ageing. We propose establishing, overseeing, and implementing strategic investments in model development, tools, resources, and ethical frameworks for accelerating progress towards therapeutic interventions for neurodegenerative diseases. We call to action governments, funding agencies, and the scientific community to expand NHP research while ensuring ethical standards and public engagement to maximise its potential for tackling age-related neurodegenerative diseases. We propose to support the set-up of an international research consortium to pool knowledge, expertise, and resources to tackle frontier-breaking scientific questions.
Acknowledgements
The PD-AGE consortium was funded by the Michael J. Fox Foundation (Grant N°022769). We thank all members of PD-AGE.
Author contributions
E.B., R.M.A., R.A.B., H.B., A.B., S.B., M.E.E., J.H.K., J.Y.L., A.C.M., J.M.M., Y.S., M.T., J.T., R.T., and B.D. contributed to the concepts elaborated in this position paper, contributed to the writing, and have read and approved the paper.
Data availability
No datasets were generated or analysed during the current study.
Competing interests
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
1. Bezard, E et al. Modeling Parkinson’s Disease in Primates. Cold Spring Harb. Perspect. Med.; 2025; 15, a041612.
2. Emborg, ME. Nonhuman primate models of Parkinson’s disease. ILAR J.; 2007; 48, pp. 339-355.1:CAS:528:DC%2BD2sXhtVSns73E
3. Isidro, F. Brain aging and Alzheimer’s disease, a perspective from non-human primates. Aging (Albany NY); 2024; 16, pp. 13145-13171.1:CAS:528:DC%2BB2cXis1yntrvL
4. Teil, M; Arotcarena, ML; Dehay, B. A new rise of non-human primate models of synucleinopathies. Biomedicines; 2021; 9, 272.1:CAS:528:DC%2BB3MXhtlyhurbN
5. Verdier, JM et al. Lessons from the analysis of nonhuman primates for understanding human aging and neurodegenerative diseases. Front. Neurosci.; 2015; 9, 64.
6. Aziz, TZ; Peggs, D; Sambrook, MA; Crossman, AR. Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism in the primate. Mov. Disord.; 1991; 6, pp. 288-292.1:STN:280:DyaK387gtVSksA%3D%3D
7. Wichmann, T; Bergman, H; DeLong, MR. The primate subthalamic nucleus. I. Functional properties in intact animals. J. Neurophysiol.; 1994; 72, pp. 494-506.1:STN:280:DyaK2M%2FnsVKmug%3D%3D
8. Bergman, H; Wichmann, T; Karmon, B; DeLong, MR. The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of Parkinsonism. J. Neurophysiol.; 1994; 72, pp. 507-520.1:STN:280:DyaK2M%2FnsVKmuw%3D%3D
9. Wichmann, T; Bergman, H; DeLong, MR. The primate subthalamic nucleus. III. Changes in motor behavior and neuronal activity in the internal pallidum induced by subthalamic inactivation in the MPTP model of Parkinsonism. J. Neurophysiol.; 1994; 72, pp. 521-530.1:STN:280:DyaK2M%2FnsVKlsg%3D%3D
10. Mitchell, IJ et al. Neural mechanisms underlying Parkinsonian symptoms based upon regional uptake of 2-deoxyglucose in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroscience; 1989; 32, pp. 213-226.1:CAS:528:DyaK3MXhtF2lt7k%3D
11. Albin, RL; Young, AB; Penney, JB. The functional anatomy of basal ganglia disorders. Trends Neurosci.; 1989; 12, pp. 366-375.1:STN:280:DyaK3c%2FltVGjsA%3D%3D
12. Bergman, H; Wichmann, T; DeLong, MR. Reversal of experimental Parkinsonism by lesions of the subthalamic nucleus. Science; 1990; 249, pp. 1436-1438.1:STN:280:DyaK3czosFartg%3D%3D
13. Benazzouz, A; Gross, C; Feger, J; Boraud, T; Bioulac, B. Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys. Eur. J. Neurosci.; 1993; 5, pp. 382-389.1:STN:280:DyaK2c%2FosValtQ%3D%3D
14. Benabid, AL et al. Acute and long-term effects of subthalamic nucleus stimulation in Parkinson’s disease. Stereotact. Funct. Neurosurg.; 1994; 62, pp. 76-84.1:STN:280:DyaK2MzlslGluw%3D%3D
15. Pollak, P et al. Effects of the stimulation of the subthalamic nucleus in Parkinson disease. Rev. Neurol. (Paris); 1993; 149, pp. 175-176.1:STN:280:DyaK2c%2Fltlagsw%3D%3D
16. Rhesus Macaque Genome, S et al. Evolutionary and biomedical insights from the Rhesus macaque genome. Science; 2007; 316, pp. 222-234.
17. Strange, BA; Witter, MP; Lein, ES; Moser, EI. Functional organization of the hippocampal longitudinal axis. Nat. Rev. Neurosci.; 2014; 15, pp. 655-669.1:CAS:528:DC%2BC2cXhsFOksrvE
18. Roelfsema, PR; Treue, S. Basic neuroscience research with nonhuman primates: a small but indispensable component of biomedical research. Neuron; 2014; 82, pp. 1200-1204.1:CAS:528:DC%2BC2cXhtVCju7jN
19. Wallis, JD. Cross-species studies of orbitofrontal cortex and value-based decision-making. Nat. Neurosci.; 2011; 15, pp. 13-19.
20. Preuss, TM; Wise, SP. Evolution of prefrontal cortex. Neuropsychopharmacology; 2022; 47, pp. 3-19.
21. Herculano-Houzel, S. The human brain in numbers: a linearly scaled-up primate brain. Front. Hum. Neurosci.; 2009; 3, 31.
22. Phillips, KA et al. Why primate models matter. Am. J. Primatol.; 2014; 76, pp. 801-827.
23. Friedman, H et al. The critical role of nonhuman primates in medical research. Pathog. Immun.; 2017; 2, pp. 352-365.
24. Balasubramanian, P; Howell, PR; Anderson, RM. Aging and caloric restriction research: a biological perspective with translational potential. EBioMedicine; 2017; 21, pp. 37-44.
25. Souder, DC et al. Rhesus monkeys as a translational model for late-onset Alzheimer’s disease. Aging Cell; 2021; 20, e13374.1:CAS:528:DC%2BB3MXhtVajsbzO
26. Walker, ML. Menopause in female rhesus monkeys. Am. J. Primatol.; 1995; 35, pp. 59-71.
27. Bellino, FL; Wise, PM. Nonhuman primate models of menopause workshop. Biol. Reprod.; 2003; 68, pp. 10-18.1:CAS:528:DC%2BD3sXjtVyj
28. Herrero, MT et al. Does neuromelanin contribute to the vulnerability of catecholaminergic neurons in monkeys intoxicated with MPTP?. Neuroscience; 1993; 56, pp. 499-511.1:CAS:528:DyaK3sXmsVehsLo%3D
29. Mann, DM; Yates, PO. Possible role of neuromelanin in the pathogenesis of Parkinson’s disease. Mech. Ageing Dev.; 1983; 21, pp. 193-203.1:CAS:528:DyaL3sXkt1Smu7k%3D
30. Emborg, ME et al. Age-related declines in nigral neuronal function correlate with motor impairments in rhesus monkeys. J. Comp. Neurol.; 1998; 401, pp. 253-265.1:CAS:528:DyaK1cXntlamu7o%3D
31. Walker, LC; Jucker, M. The exceptional vulnerability of humans to Alzheimer’s disease. Trends Mol. Med.; 2017; 23, pp. 534-545.
32. Lundblad, M et al. Pharmacological validation of a mouse model of l-DOPA-induced dyskinesia. Exp. Neurol.; 2005; 194, pp. 66-75.1:CAS:528:DC%2BD2MXkt1GisrY%3D
33. Bastide, MF et al. Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson’s disease. Prog. Neurobiol.; 2015; 132, pp. 96-168.1:CAS:528:DC%2BC2MXht1Crsr3I
34. Mattison, JA; Vaughan, KL. An overview of nonhuman primates in aging research. Exp. Gerontol.; 2017; 94, pp. 41-45.
35. Percie du Sert, N et al. The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol.; 2020; 18, e3000410.1:CAS:528:DC%2BB3cXhsVeqtL3P
36. Tremblay, S et al. An open resource for non-human primate optogenetics. Neuron; 2020; 108, pp. 1075-1090.e1076.1:CAS:528:DC%2BB3cXitFGrtL3O
37. Niu, Y et al. Early Parkinson’s disease symptoms in alpha-synuclein transgenic monkeys. Hum. Mol. Genet; 2015; 24, pp. 2308-2317.1:CAS:528:DC%2BC2MXhsVOhsLbE
38. Ando, K et al. PET analysis of dopaminergic neurodegeneration in relation to immobility in the MPTP-treated common marmoset, a model for Parkinson’s disease. PLoS ONE; 2012; 7, e46371.1:CAS:528:DC%2BC38XhsFCitr3N
39. Recasens, A et al. Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys. Ann. Neurol.; 2014; 75, pp. 351-362.1:CAS:528:DC%2BC2cXlvVSjt7k%3D
40. Bourdenx, M et al. Identification of distinct pathological signatures induced by patient-derived alpha-synuclein structures in nonhuman primates. Sci. Adv.; 2020; 6, eaaz9165.1:CAS:528:DC%2BB3cXitFGgs7vL
41. Kinet, R et al. Differential pathological dynamics triggered by distinct Parkinson patient-derived alpha-synuclein extracts in nonhuman primates. Sci. Adv.; 2025; 11, eadu6050.1:CAS:528:DC%2BB2MXhsVOqtb3L
42. Chu, Y et al. Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes. Brain; 2019; 142, pp. 3565-3579.
43. Sawamura, M et al. Lewy body disease primate model with alpha-synuclein propagation from the olfactory bulb. Mov. Disord.; 2022; 37, pp. 2033-2044.1:CAS:528:DC%2BB38Xit1emsbbI
44. Shimozawa, A et al. Propagation of pathological alpha-synuclein in marmoset brain. Acta Neuropathol. Commun.; 2017; 5, 12.
45. Fayard, A et al. Functional and neuropathological changes induced by injection of distinct alpha-synuclein strains: a pilot study in non-human primates. Neurobiol. Dis.; 2023; 180, 106086.1:CAS:528:DC%2BB3sXmtleis7o%3D
46. Guo, JJ et al. Intranasal administration of alpha-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis. Cell Death Dis.; 2021; 12, 1:CAS:528:DC%2BB3MXltlakurc%3D 81.
47. Bezard, E et al. Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson’s disease. J. Neurosci.; 2001; 21, pp. 6853-6861.1:CAS:528:DC%2BD3MXmt1Wis7o%3D
48. Kordower, JH et al. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science; 2000; 290, pp. 767-773.1:CAS:528:DC%2BD3cXns1akur4%3D
49. Kordower, JH; Fiandaca, MS; Notter, MF; Hansen, JT; Gash, DM. NGF-like trophic support from peripheral nerve for grafted rhesus adrenal chromaffin cells. J. Neurosurg.; 1990; 73, pp. 418-428.1:STN:280:DyaK3czkslGitQ%3D%3D
50. Hantraye, P et al. In vivo” visualization by positron emission tomography of the progressive striatal dopamine receptor damage occurring in MPTP-intoxicated non-human primates. Life Sci.; 1986; 39, pp. 1375-1382.1:CAS:528:DyaL28Xmt1Wrt70%3D
51. Kikuchi, T et al. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature; 2017; 548, pp. 592-596.1:CAS:528:DC%2BC2sXhsVektrbM
52. Chocarro, J et al. Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates. Brain; 2023; 146, pp. 5000-5014.
53. Kirik, D et al. Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson’s disease. Proc. Natl Acad. Sci. USA; 2003; 100, pp. 2884-2889.1:CAS:528:DC%2BD3sXitVaitbY%3D
54. Wianny, F et al. Induced cognitive impairments reversed by grafts of neural precursors: a longitudinal study in a macaque model of Parkinson’s disease. Adv. Sci. (Weinh.); 2022; 9, e2103827.
55. Blesa, J et al. The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: a PET, histological and biochemical study. Neurobiol. Dis.; 2012; 48, pp. 79-91.1:CAS:528:DC%2BC38XhtFKmsrvO
56. Ballanger, B et al. Imaging dopamine and serotonin systems on MPTP monkeys: a longitudinal PET investigation of compensatory mechanisms. J. Neurosci.; 2016; 36, pp. 1577-1589.1:CAS:528:DC%2BC28Xpt1OjsLs%3D
57. Metzler, LAP; Metzger, JM; Gerred, KJ; Emborg, ME; Kapoor, A. Expression patterns of blood-based biomarkers of neurodegeneration and inflammation across adulthood in rhesus macaques. Exp. Gerontol.; 2025; 203, 112736.1:CAS:528:DC%2BB2MXns1CgsLs%3D
58. Wichmann, T; DeLong, MR. Pathophysiology of Parkinson’s disease: the MPTP primate model of the human disorder. Ann. N. Y Acad. Sci.; 2003; 991, pp. 199-213.1:CAS:528:DC%2BD3sXmtVCku7Y%3D
59. Jennings, CG et al. Opportunities and challenges in modeling human brain disorders in transgenic primates. Nat. Neurosci.; 2016; 19, pp. 1123-1130.
60. Liang, W et al. Gene editing monkeys: retrospect and outlook. Front. Cell Dev. Biol.; 2022; 10, 913996.
61. Halliday, GM; Leverenz, JB; Schneider, JS; Adler, CH. The neurobiological basis of cognitive impairment in Parkinson’s disease. Mov. Disord.; 2014; 29, pp. 634-650.1:CAS:528:DC%2BC2cXmvVyqt70%3D
62. Schneider, J. S. Modeling cognitive deficits associated with parkinsonism in the chronic-low-dose MPTP-treated monkey. in: Animal Models of Cognitive Impairment, Levin, E. D. & Buccafusco, J. J. (eds) (Boca Raton (FL), 2006).
63. Mosharov, E. V. et al. A human brain map of mitochondrial respiratory capacity and diversity. Nature641, 749–758 (2025).
64. Emborg, ME. Reframing the perception of outliers and negative data in translational research. Brain Res. Bull.; 2023; 192, pp. 203-207.
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
© The Author(s) 2025. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the "License"). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Abstract
The PD-AGE international task force underscores the pivotal role that non-human primate (NHP) models play in advancing our understanding of Parkinson’s disease (PD) and ageing. Due to their close genetic, anatomical, and behavioural similarity to humans, NHPs uniquely enable translational research to bridge basic science towards clinical application. They are indispensable for modelling the complex motor and non-motor symptoms of PD, as well as age-related neurodegeneration. This paper outlines the scientific rationale, methodological strengths, and ethical considerations surrounding NHP use in PD research. We highlight the need for standardised models, innovative tools, and long-term collaborative infrastructure to enhance the translational value of NHP studies. We propose a three-phase roadmap to develop a global research consortium to optimise resource use, improve model fidelity, and accelerate therapeutic development for PD and related neurodegenerative disorders.
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
Details
1 Univ. Bordeaux, CNRS, IMN, UMR 5293, F-33000, Bordeaux, France (ROR: https://ror.org/057qpr032) (GRID: grid.412041.2) (ISNI: 0000 0001 2106 639X)
2 Division of Geriatrics, Department of Medicine, SMPH, University of Wisconsin-Madison, & GRECC, William S Middleton Memorial Veterans Hospital, Madison, WI, USA (ROR: https://ror.org/037xafn82) (GRID: grid.417123.2) (ISNI: 0000 0004 0420 6882)
3 Commissariat à l’Energie Atomique (CEA), Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France (ROR: https://ror.org/010j2gw05) (GRID: grid.457349.8) (ISNI: 0000 0004 0623 0579)
4 The Edmond and Lily Safra Center for Brain Science, The Hebrew University, Jerusalem, Israel (ROR: https://ror.org/03qxff017) (GRID: grid.9619.7) (ISNI: 0000 0004 1937 0538)
5 ASU-Banner Neurodegenerative Disease Research Center, Arizona State University, 85281, Tempe, AZ, USA (ROR: https://ror.org/03efmqc40) (GRID: grid.215654.1) (ISNI: 0000 0001 2151 2636)
6 Department of Neurosciences and Movement Sciences, University of Fribourg, Fribourg, Switzerland (ROR: https://ror.org/022fs9h90) (GRID: grid.8534.a) (ISNI: 0000 0004 0478 1713); Center for the Neural Basis of Cognition, Department of Bioengineering, University of Pittsburgh, 15261, Pittsburgh, PA, USA (ROR: https://ror.org/01an3r305) (GRID: grid.21925.3d) (ISNI: 0000 0004 1936 9000)
7 Preclinical Parkinson’s Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, 53715, Madison, WI, USA (ROR: https://ror.org/01y2jtd41) (GRID: grid.14003.36) (ISNI: 0000 0001 2167 3675); Department of Medical Physics, University of Wisconsin-Madison, 53715, Madison, WI, USA (ROR: https://ror.org/01y2jtd41) (GRID: grid.14003.36) (ISNI: 0000 0001 2167 3675)
8 Laboratory of Research in Parkinson’s Disease and Related Disorders, Health Sciences Institute, China Medical University, Shenyang, China (ROR: https://ror.org/00v408z34) (GRID: grid.254145.3) (ISNI: 0000 0001 0083 6092); Neural Plasticity and Repair Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden (ROR: https://ror.org/012a77v79) (GRID: grid.4514.4) (ISNI: 0000 0001 0930 2361)
9 Department of Neurology, Emory National Primate Research Center, Emory University, 954, Gatewood Rd NE, 30329, Atlanta, GA, USA (ROR: https://ror.org/03czfpz43) (GRID: grid.189967.8) (ISNI: 0000 0001 0941 6502)
10 Preclinical Parkinson’s Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, 53715, Madison, WI, USA (ROR: https://ror.org/01y2jtd41) (GRID: grid.14003.36) (ISNI: 0000 0001 2167 3675)
11 Department of Neurology, Graduate School of Medicine, Osaka University, Suita, 565-0871, Osaka, Japan (ROR: https://ror.org/035t8zc32) (GRID: grid.136593.b) (ISNI: 0000 0004 0373 3971)
12 Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan (ROR: https://ror.org/02kpeqv85) (GRID: grid.258799.8) (ISNI: 0000 0004 0372 2033)
13 Kyoto University Office of Research Acceleration (KURA), 606-8501, Kyoto, Japan (ROR: https://ror.org/02kpeqv85) (GRID: grid.258799.8) (ISNI: 0000 0004 0372 2033)