Periodic Reporting for period 3 - AND-PD (COMORBIDITY MECHANISMS OF ANXIETY AND PARKINSON’S DISEASE)
Okres sprawozdawczy: 2023-01-01 do 2024-06-30
The AND-PD project explored the underlying mechanisms of anxiety (with or without depression) as a non-motor co-morbidity of Parkinson’s Disease (PD). The aim was to understand how PD leads to functional and pathological changes in the midbrain. The findings offer new insights to advance the personalised treatment of PD patients and open new research directions for preventing, diagnosing and managing co-morbidities in PD patients.
Using PD models, AND-PD studied the appearance of comorbid symptoms like anxiety and depression, along with functional changes in midbrain nuclei, establishing a link with the anxiety phenotype. These findings were used to inform pre-clinical (rodent, non-human primate and biobank samples) and clinical research (fMRI and PET imaging, behavioural analysis, retrospective cohort analysis) to identify and correlate causalities between dysfunctional neurocircuitry and co-morbid anxiety in PD. To investigate causality, the AND-PD project has undertaken the following approaches:
1. Analysed Anxiety in PD Models: Studied anxiety symptoms using both neurotoxin-induced and genetic models of PD.
2. Assessed Brainstem Damage: Evaluated the physiological and behavioural effects of interventions that specifically replicate PD-related damage in the brainstem.
3. Explored RNA-Based Approaches: Tested the effectiveness of RNA-based methods in reducing anxiety associated with PD.
In addition to these experimental approaches, AND-PD has examined the connection in human patients by:
1. Analysing Patient Databases: Correlated anxiety measures with signs of neuropathology in the brainstem of PD brain samples.
2. Using Brainstem Imaging: Linked clinical and functional biomarkers of dysfunctional neurotransmission, identified through brainstem imaging, with anxiety symptoms in patients.
The expertise of AND-PD beneficiaries in translational research played a crucial role in bridging the gap between preclinical and clinical studies and helped to identify new anatomical targets and markers—whether molecular, functional, or pathological—to support better diagnosis, management, and treatment of co-morbidities in PD patients.
Using PD models, AND-PD studied the appearance of comorbid symptoms like anxiety and depression, along with functional changes in midbrain nuclei, establishing a link with the anxiety phenotype. These findings were used to inform pre-clinical (rodent, non-human primate and biobank samples) and clinical research (fMRI and PET imaging, behavioural analysis, retrospective cohort analysis) to identify and correlate causalities between dysfunctional neurocircuitry and co-morbid anxiety in PD. To investigate causality, the AND-PD project has undertaken the following approaches:
1. Analysed Anxiety in PD Models: Studied anxiety symptoms using both neurotoxin-induced and genetic models of PD.
2. Assessed Brainstem Damage: Evaluated the physiological and behavioural effects of interventions that specifically replicate PD-related damage in the brainstem.
3. Explored RNA-Based Approaches: Tested the effectiveness of RNA-based methods in reducing anxiety associated with PD.
In addition to these experimental approaches, AND-PD has examined the connection in human patients by:
1. Analysing Patient Databases: Correlated anxiety measures with signs of neuropathology in the brainstem of PD brain samples.
2. Using Brainstem Imaging: Linked clinical and functional biomarkers of dysfunctional neurotransmission, identified through brainstem imaging, with anxiety symptoms in patients.
The expertise of AND-PD beneficiaries in translational research played a crucial role in bridging the gap between preclinical and clinical studies and helped to identify new anatomical targets and markers—whether molecular, functional, or pathological—to support better diagnosis, management, and treatment of co-morbidities in PD patients.
The central hypothesis of AND-PD is that PD is associated with DRN microcircuit dysfunction caused by the functional decline of dopaminergic neurons in the DRN, leading to PD-related anxiety/depression.
To test the hypothesis, several different PD models were validated in the project. The Aphakia and Glong mouse models were found to be useful for studying depression and anxiety in PD, whereas the MPTP mice model was ineffective. However, administering MPTP to nonhuman primates was found to help researchers study the anxiety/depression phenotype.
Stereological and morphological evidence in these pre-clinical models suggested that dopaminergic neurone degradation in the DRN is responsible for comorbid anxiety in PD. The results also suggested the presence of a complex connectivity pattern, with the basolateral amygdala as a synaptic hub between DRN and the DS, involving different neuromodulatory systems to modulate anxiety and depression-like responses.
Our results also revealed that single target SINEUPs can increase endogenous expressions of the neuroprotective factor Gdnf and its receptor, providing a new tool for increasing the neuroprotection of DA neurons and a new path for PD drug development.
Our research also showed that three DA cell subtypes can be identified using single cell RNA expression data. In mice models, we were able to provoke a change in the expression of genes involved in neuronal differentiation, immune system response, and inflammation. Inflammation, in particular, was linked to depression in PD individuals, providing a scientific foundation for further research into the role of inflammation in the pathogenesis of depression in PD models.
In human brain samples of patients with PD, our research identified that a history of comorbidity of anxiety and depression was consistently associated with a higher rate of dopaminergic cell loss in the DRN, providing important support for the role of dopaminergic neuron degeneration in these PD comorbidities. We discovered that patients diagnosed with anxiety in later life are more likely to be diagnosed with PD, and there are specific clinical features that identify those with anxiety at increased risk of PD. We also found that the development of anxiety in patients with PD is caused by both dopaminergic deficit in the basal ganglia and non-dopaminergic or extrastriatal pathology, which is consistent with the pre-clinical studies.
Finally, in the imaging study in human participants, AND-PD created normative maps of the dopaminergic and serotonergic systems for PET image analysis, which will be invaluable in the study of anxiety and depression, as well as other research of these systems across disease areas.
To test the hypothesis, several different PD models were validated in the project. The Aphakia and Glong mouse models were found to be useful for studying depression and anxiety in PD, whereas the MPTP mice model was ineffective. However, administering MPTP to nonhuman primates was found to help researchers study the anxiety/depression phenotype.
Stereological and morphological evidence in these pre-clinical models suggested that dopaminergic neurone degradation in the DRN is responsible for comorbid anxiety in PD. The results also suggested the presence of a complex connectivity pattern, with the basolateral amygdala as a synaptic hub between DRN and the DS, involving different neuromodulatory systems to modulate anxiety and depression-like responses.
Our results also revealed that single target SINEUPs can increase endogenous expressions of the neuroprotective factor Gdnf and its receptor, providing a new tool for increasing the neuroprotection of DA neurons and a new path for PD drug development.
Our research also showed that three DA cell subtypes can be identified using single cell RNA expression data. In mice models, we were able to provoke a change in the expression of genes involved in neuronal differentiation, immune system response, and inflammation. Inflammation, in particular, was linked to depression in PD individuals, providing a scientific foundation for further research into the role of inflammation in the pathogenesis of depression in PD models.
In human brain samples of patients with PD, our research identified that a history of comorbidity of anxiety and depression was consistently associated with a higher rate of dopaminergic cell loss in the DRN, providing important support for the role of dopaminergic neuron degeneration in these PD comorbidities. We discovered that patients diagnosed with anxiety in later life are more likely to be diagnosed with PD, and there are specific clinical features that identify those with anxiety at increased risk of PD. We also found that the development of anxiety in patients with PD is caused by both dopaminergic deficit in the basal ganglia and non-dopaminergic or extrastriatal pathology, which is consistent with the pre-clinical studies.
Finally, in the imaging study in human participants, AND-PD created normative maps of the dopaminergic and serotonergic systems for PET image analysis, which will be invaluable in the study of anxiety and depression, as well as other research of these systems across disease areas.
At present the symptomatology, chronopathology, and neurobiology of anxiety in PD are all poorly understood, which hinders accurate diagnosis and the development of effective treatment strategies. It is estimated that the prevalence of anxiety disorders in patients with PD could be as high as 40%. Although it is recognised that anxiety adds to the complexity of PD, lowers patients’ quality of life and can be exacerbated by conventional anti-Parkinson’s treatments, there is a significant paucity of clinical data for this population. AND-PD is testing a completely novel hypothesis regarding the neurobiology underlying the connection between PD and anxiety.
Animal models are an essential tool to investigate mechanisms of PD and potential therapeutic approaches. However, due to the complexity of PD, current models reproduce only in part the distribution and temporal evolution of the neurodegenerative processes and associated motor and non-motor symptoms. AND-PD has begun to characterize existing models of PD testing for anxiety and depression in order to establish PD models with mental comorbidities. Furthermore, ANP-PD has also began to generate novel genetic models of PD, which will identify for the first time the neural circuitry that underlies comorbid anxiety in PD.
Through the clinical and imaging studies in patients with PD, we will make major contributions to the understanding of the underlying pathophysiology of anxiety in PD, in an area whether there is currently very little understanding of biological processes, imaging and clinical features, time course, correlation and treatment response.
Animal models are an essential tool to investigate mechanisms of PD and potential therapeutic approaches. However, due to the complexity of PD, current models reproduce only in part the distribution and temporal evolution of the neurodegenerative processes and associated motor and non-motor symptoms. AND-PD has begun to characterize existing models of PD testing for anxiety and depression in order to establish PD models with mental comorbidities. Furthermore, ANP-PD has also began to generate novel genetic models of PD, which will identify for the first time the neural circuitry that underlies comorbid anxiety in PD.
Through the clinical and imaging studies in patients with PD, we will make major contributions to the understanding of the underlying pathophysiology of anxiety in PD, in an area whether there is currently very little understanding of biological processes, imaging and clinical features, time course, correlation and treatment response.