Alexus Jackson 1
1 Department of Biological Sciences, San Jose State University, San Jose, CA 95112
Abstract
Neurodegenerative diseases have debilitating consequences for the health and longevity of the nervous system. Parkinson’s disease (PD) is one of the most common neurodegenerative disorders with a typical onset between ages 55 and 65 that results from dopamine depletion in the brain. This dopamine loss occurs in the substantia nigra compacta (SNc), which accordingly is the target for many dopamine regeneration techniques. Additionally, several studies have suggested that an accumulation of the large protein, α-synuclein, is responsible for the loss of dopamine in this region. However, the association between α-synuclein and dopamine remains an active area of research. While there is no cure for the disease, pharmacological and surgical treatments have been developed to alleviate PD’s motor and non-motor symptoms. Currently, successful outcomes in experimental models provide hope for the effectiveness of cell therapy in the regeneration of dopamine. However, further investigation is needed to determine its effectiveness in humans. This literature review will highlight current progress in the efforts to restore and prevent the loss of dopamine in the brain as an avenue to treat PD. Among these are dopamine replacement therapy (DRT), Gemfibrozil and carotid body (CB) transplantation.
Introduction
Parkinson’s disease (PD) results from the degeneration of dopaminergic neurons throughout the brain (Damier et al. 1999). Patients with PD can experience both motor and non-motor symptoms. Dopamine loss is associated with cardinal motor symptoms including tremors, bradykinesia, rigidity and postural instability (Yang et al. 2020). In addition, PD patients can develop non-motor symptoms, including cognitive dysfunction, where individuals experience impairments in memory, executive function and slower thinking (Decourt et al. 2021). Both motor and non-motor symptoms in PD should not be dichotomized. A study by Wojtala et al. (2018) demonstrated that individuals with a particular motor symptom are more likely to experience a non-motor symptom unique to their motor symptom. This finding, and the continued characterization of how motor symptoms relate to non-motor symptoms, provide detailed pathophysiology and clinical characteristics of PD.
In addition to the aforementioned non-motor symptoms of PD, neuroendocrine abnormalities have been identified as a symptom of the disease (Pablo-Fernández et al. 2017). These abnormalities include homeostatic imbalance caused by changes in both hormone secretion and circadian rhythm. To date, neuroendocrine abnormalities in PD are still poorly understood despite being a common symptom. Understanding unique neuroendocrine abnormalities can inform clinicians of how to best provide personalized care to improve patients’ quality of life. This review will discuss the complex and multifactorial characteristics of PD. Researchers have explored a wide range of treatment options to address this complex disease. Those that appear to be innovative and promising for the rejuvenation of dopamine in the substantia nigra compacta (SNc), the region of the brain most affected by dopamine loss, were highlighted. The intricate relationship between motor phenotypes and cognitive function were also reviewed, highlighting the implications of neuroendocrine abnormalities, and providing an analysis of brain regions that endure dopamine loss. Lastly, the current state of pharmacological treatment to reverse dopamine loss was discussed, in order to provide researchers with a detailed framework for the future development of tailored clinical assessments and symptom-specific therapy.
The interconnectedness of motor phenotypes and cognitive function in Parkinson’s disease
The onset of Parkinson’s disease is characterized by several well-known motor symptoms such as tremors, bradykinesia and motor rigidity. Meanwhile, PD’s motor symptoms also include a breadth of non-motor symptoms such as constipation, sleep disturbance, pain, anxiety and cognitive decline. PD-related cognitive decline could manifest in changes in attention, memory, visuospatial, executive and language functions (Kwon et al. 2022). Recent studies suggest that motor and non-motor symptoms in PD may have some influence over one another. Certain motor symptoms, such as olfactory and cognitive declines are highly correlated with dementia (Yang et al. 2021).
Motor phenotypes can be classified based on an individual’s most debilitating symptom: 1) tremor-dominant (TR-D) and 2) postural instability and gait difficulty (PIGD). The tremor-dominant phenotype is characterized by resting or postural tremors, while the PIGD phenotype is characterized by slowness of movement and an inability to move one’s muscles (Wojtala et al. 2019).
Wojtala et al. (2019) examined the aforementioned categories of motor symptoms and their relationship with cognitive function using the Unified Parkinson’s disease Rating Scale, a metric used to conduct motor evaluation along the longitudinal course of PD. Their analyses of 538 PD patients, organized according to their motor and cognitive phenotypes, revealed a distinct relationship between an individual’s motor symptoms and cognitive function. PIGD patients experienced significantly more cognitive impairment, in terms of attention and memory than TR-D patients. TR-D patients performed worse on cognitive test scores in activities such as digit span, word fluency and attention than patients within the ND designation. Meanwhile, PIGD patients suffered significantly more difficulty in categories of word fluency, working memory and sorting abilities than TR-D patients.
In a separate study, Yang et al. (2021) categorized their patient cohort by their motor symptoms to assess the presence of any associated cognitive defects. Consistent with Wojtala et al. (2019), their group found that PIGD patients were at a higher risk of suffering from cognitive deficits, specifically verbal fluency. Yang et al. (2021) conceded that a longitudinal study will better inform the nuanced relationship between motor phenotype and cognitive function, hypothesizing that the motor symptoms of PD patients may gradually evolve. For example, an individual with symptoms of PIGD at the time of diagnosis, may later develop TR-D.
A recent study by Voruz et al. (2022) examined the nuanced relationship between motor and non-motor symptoms, indicating that deficits in certain non-motor symptoms may depend on whether an individual with PD is predominantly afflicted with either left (LPD) or right (RPD) motor symptoms. The distinction between LPD and RPD motor symptoms indicates the potential for unilateral motor symptom development, and, consequently, a variation in the relationships between non-motor symptoms and motor phenotypes. Voruz et al. (2022) identified the presence of asymmetrical cognitive impairment across PD patients with predominantly left or right motor symptoms. The cohort of individuals under study in this experiment included: 1) predominantly left-sided motor symptoms at diagnosis, n = 179, 2) right-sided motor symptoms at diagnosis, n = 234 and 3) healthy controls, n = 196. Individual data were collected over the span of three years.
The investigators were able to observe significant differences in the cohort’s motor symptoms and revealed that RPD and LPD individuals did not present any significant differences in cognition and neuropsychiatry concentrations at Year 1 measurements. However, at Year 3, distinct differences were noted. Firstly, RPD patients demonstrated a slight decrease in performance on the Hopkins Verbal Learning Test. Secondly, both LPD and RPD groups performed significantly worse than healthy controls in the Symbol Digit test. Thirdly, RPD individuals presented a decrease over time in cognitive global efficiency. And lastly, LPD individuals exhibited significantly more depressive symptoms than their RPD counterparts. In all, their findings suggest that at the time of PD onset, patients may develop cognitive and neuropsychiatric deficits that occur as a result of their motor symptoms.
The complexity of motor and non-motor symptoms extends to PD patients with and without mild cognitive impairment (MCI). In an effort to sort through the heterogeneity of PD symptoms and cognitive decline, Kehagia et al. (2013) formulated the “dual syndrome hypothesis.” This hypothesis states that MCI in PD is related to dopaminergic deficits, whereas dementia in PD is linked to cholinergic deficits. The existence of varying cognitive deficits with multiple potential causes indicates that neurodegeneration is heterogeneous among individuals. This observation also implies that there may not be a concrete, distinctive relationship between non-motor and motor symptoms.
A study by Kwon et al. (2022) investigated the risk factors associated with MCI in PD patients and the relationships between each cognitive deficit with these risk factors in patients with de novo PD. Their results showed that individuals with MCI and PD had higher rigidity scores and lower cognitive function than those without MCI. These measurements were performed using the Unified Parkinson’s Disease Rating Scale (UPDRS-III) and the Hoehn and Yahr Stage (HY Stage), respectively. In addition to compromised motor capabilities, PD individuals with MCI also experienced more depression and dysautonomia, a disorder of the autonomic nervous system. Kwon et al. (2022) attributed the wide association of motor symptoms and cognitive function in these patients to both their dopaminergic and non-dopaminergic neurodegeneration that occurs throughout the disease’s progression.
Recent studies have indicated that there are strong associations between motor and non-motor symptoms in patients with PD. Additionally, individuals with specific motor subtypes such as PIGD or TR-D may suffer from various cognitive deficiencies that are strongly associated with their specific motor phenotype. A 3-year longitudinal study suggested that cognitive deficiency, and therefore, the presentation of non-motor symptoms can be dependent on whether or not their motor symptoms are predominantly right or left-sided. The relationship between motor and non-motor symptoms in individuals with PD is extremely complex and multifactorial. Therefore, longitudinal studies that utilize repetitive measurements and take into account are necessary to provide well-rounded and well-informed data that capture the heterogeneity of Parkinson’s Disease.
The investigators were able to observe significant differences in the cohort’s motor symptoms and revealed that RPD and LPD individuals did not present any significant differences in cognition and neuropsychiatry concentrations at Year 1 measurements. However, at Year 3, distinct differences were noted. Firstly, RPD patients demonstrated a slight decrease in performance on the Hopkins Verbal Learning Test. Secondly, both LPD and RPD groups performed significantly worse than healthy controls in the Symbol Digit test. Thirdly, RPD individuals presented a decrease over time in cognitive global efficiency. And lastly, LPD individuals exhibited significantly more depressive symptoms than their RPD counterparts. In all, their findings suggest that at the time of PD onset, patients may develop cognitive and neuropsychiatric deficits that occur as a result of their motor symptoms.
The complexity of motor and non-motor symptoms extends to PD patients with and without mild cognitive impairment (MCI). In an effort to sort through the heterogeneity of PD symptoms and cognitive decline, Kehagia et al. (2013) formulated the “dual syndrome hypothesis.” This hypothesis states that MCI in PD is related to dopaminergic deficits, whereas dementia in PD is linked to cholinergic deficits. The existence of varying cognitive deficits with multiple potential causes indicates that neurodegeneration is heterogeneous among individuals. This observation also implies that there may not be a concrete, distinctive relationship between non-motor and motor symptoms.
A study by Kwon et al. (2022) investigated the risk factors associated with MCI in PD patients and the relationships between each cognitive deficit with these risk factors in patients with de novo PD. Their results showed that individuals with MCI and PD had higher rigidity scores and lower cognitive function than those without MCI. These measurements were performed using the Unified Parkinson’s Disease Rating Scale (UPDRS-III) and the Hoehn and Yahr Stage (HY Stage), respectively. In addition to compromised motor capabilities, PD individuals with MCI also experienced more depression and dysautonomia, a disorder of the autonomic nervous system. Kwon et al. (2022) attributed the wide association of motor symptoms and cognitive function in these patients to both their dopaminergic and non-dopaminergic neurodegeneration that occurs throughout the disease’s progression.
Recent studies have indicated that there are strong associations between motor and non-motor symptoms in patients with PD. Additionally, individuals with specific motor subtypes such as PIGD or TR-D may suffer from various cognitive deficiencies that are strongly associated with their specific motor phenotype. A 3-year longitudinal study suggested that cognitive deficiency, and therefore, the presentation of non-motor symptoms can be dependent on whether or not their motor symptoms are predominantly right or left-sided. The relationship between motor and non-motor symptoms in individuals with PD is extremely complex and multifactorial. Therefore, longitudinal studies that utilize repetitive measurements and take into account are necessary to provide well-rounded and well-informed data that capture the heterogeneity of Parkinson’s Disease.
The investigators were able to observe significant differences in the cohort’s motor symptoms and revealed that RPD and LPD individuals did not present any significant differences in cognition and neuropsychiatry concentrations at Year 1 measurements. However, at Year 3, distinct differences were noted. Firstly, RPD patients demonstrated a slight decrease in performance on the Hopkins Verbal Learning Test. Secondly, both LPD and RPD groups performed significantly worse than healthy controls in the Symbol Digit test. Thirdly, RPD individuals presented a decrease over time in cognitive global efficiency. And lastly, LPD individuals exhibited significantly more depressive symptoms than their RPD counterparts. In all, their findings suggest that at the time of PD onset, patients may develop cognitive and neuropsychiatric deficits that occur as a result of their motor symptoms.
The complexity of motor and non-motor symptoms extends to PD patients with and without mild cognitive impairment (MCI). In an effort to sort through the heterogeneity of PD symptoms and cognitive decline, Kehagia et al. (2013) formulated the “dual syndrome hypothesis.” This hypothesis states that MCI in PD is related to dopaminergic deficits, whereas dementia in PD is linked to cholinergic deficits. The existence of varying cognitive deficits with multiple potential causes indicates that neurodegeneration is heterogeneous among individuals. This observation also implies that there may not be a concrete, distinctive relationship between non-motor and motor symptoms.
A study by Kwon et al. (2022) investigated the risk factors associated with MCI in PD patients and the relationships between each cognitive deficit with these risk factors in patients with de novo PD. Their results showed that individuals with MCI and PD had higher rigidity scores and lower cognitive function than those without MCI. These measurements were performed using the Unified Parkinson’s Disease Rating Scale (UPDRS-III) and the Hoehn and Yahr Stage (HY Stage), respectively. In addition to compromised motor capabilities, PD individuals with MCI also experienced more depression and dysautonomia, a disorder of the autonomic nervous system. Kwon et al. (2022) attributed the wide association of motor symptoms and cognitive function in these patients to both their dopaminergic and non-dopaminergic neurodegeneration that occurs throughout the disease’s progression.
Recent studies have indicated that there are strong associations between motor and non-motor symptoms in patients with PD. Additionally, individuals with specific motor subtypes such as PIGD or TR-D may suffer from various cognitive deficiencies that are strongly associated with their specific motor phenotype. A 3-year longitudinal study suggested that cognitive deficiency, and therefore, the presentation of non-motor symptoms can be dependent on whether or not their motor symptoms are predominantly right or left-sided. The relationship between motor and non-motor symptoms in individuals with PD is extremely complex and multifactorial. Therefore, longitudinal studies that utilize repetitive measurements and take into account are necessary to provide well-rounded and well-informed data that capture the heterogeneity of Parkinson’s Disease.
Neuroendocrine abnormalities in individuals with Parkinson’s disease
The human neuroendocrine system is organized into the cells within an organ responsible for the excretion of hormones, transmitters and markers of various neural pathways. Neuroendocrine abnormalities are discrepancies in the neuroendocrine system, specifically those culminating in homeostatic imbalance (Pablo-Fernandez et al. 2017). Examples of these imbalances include the disruption of circadian rhythm, hormone secretion, glucose disruption and weight disturbances (Pablo-Fernandez et al. 2017).
Figure 1. A schematic of the circadian system and its dysregulation as a result of Parkinson’s disease.
Important to note is the suprachiasmatic nucleus (SCN) which serves as the central pacemaker of the circadian system. The SCN is involved in many pathways and acts as a recipient of photic information, receives cues from circulating melatonin and regulates melatonin secretion. This figure highlights the disruptive effects of Parkinson’s within shaded boxes of this figure. From “Neuroendocrine abnormalities in Parkinson’s disease,” by Pablo-Fernández et al. 2017, Journal of Neurology, Neurosurgery & Psychiatry, 88(2), 176-185. Copyright 2017 by BMJ Publishing Group Limited. Adapted with permission.
Pablo-Fernández et al. (2017) outlined a range of clinical circadian abnormalities that PD patients may suffer from (Figure 1). The first clinical circadian abnormality is an alteration to motor function whereby individuals with PD exhibit less physical activity. Such abnormalities can manifest in excessive daytime sleepiness (EDS), accompanied by increased physical activity in the evening that marks an imbalance that may be caused by dysfunctional dopaminergic release (Pablo-Fernández et al. 2017).
The result of a longitudinal study conducted by Leng et al. (2018) over the span of eleven years revealed that within a cohort with a mean age of 76.3 years, objective napping and EDS can be a predictor of PD. Those who experienced an hour or more of objective napping per day and reported EDS had a 3-fold increase in the risk of PD. Moreover, increasing napping durations are correlated with a higher risk of PD. While the study was limited to male subjects, the conclusion pointed to the importance of changes in sleep and circadian rhythms. It further posits that excessive sleepiness during the day may be a prodromal symptom of PD and a potential predictor.
The study has limitations. Periods of inactivity that extend for at least five consecutive minutes could be mistaken as periods of sleep when measured using an accelerometer (actigraph). In addition, this study relied on self-reporting to confirm physician diagnoses of PD and PD medication usage. PD diagnosis dates were lacking in this study, and the period of sleep disturbances that precede PD diagnosis was undetermined.
Non-motor functions, whereby cardiovascular circadian rhythms and internal thermal regulation are faulty and inconsistent, are another of the clinical circadian abnormalities highlighted by Pablo-Fernández et al. (2017). The last identified clinical circadian abnormalities include sleep fragmentation, insomnia, REM sleep behavior disorder (RBD), restless legs syndrome and excessive daytime sleepiness. These abnormalities are thought to be linked to pathological changes in regions of the brain that promote sleep and maintain proper rhythmic fluctuations within the brainstem, hypothalamic and subcortical and limbic regions (Kalaitzakis et al. 2013). These are common abnormalities and have considerable implications for diagnosing and treating Parkinson’s disease. While these abnormalities are better understood, the severity of these abnormalities calls for further and more intensive investigation. To date, the neuroendocrine abnormalities in PD are still poorly understood. The discovery of distinct biomarkers and other symptoms associated with neuroendocrine dysfunction can provide greater insight into PD precursors and treatment strategies.
Regions of the brain implicated in Parkinson’s disease and their relation to dopamine secretion
Gradual degeneration of regions of the midbrain and a loss of dopamine neurons within the nigrostriatal pathway are primarily implicated in the development of PD (Drui et al. 2014). Because of this, a number of studies have focused on visualizing and comparing the neuronal loss of Parkinsonian and non-Parkinsonian midbrains, specifically within the substantia nigra pars compacta (SNc). The substantia nigra is a dopaminergic nucleus in a region of the ventral midbrain made up of densely packed dopaminergic neurons (Smith and Masilamoni, 2010).. The SNc was found to be most negatively impacted by the onset of PD. In 1999, Damier et al. conducted a study using calbindin D28k immunohistochemistry that enabled the visualization of neuronal loss in five deceased individuals diagnosed with idiopathic PD. Neuronal counts of these individuals were compared to five individuals without Parkinson's disease. In addition to calbindin D28k immunostaining techniques, the group also stained for Tyrosine hydroxylase (TH-immunostaining), an enzyme responsible for converting the amino acid tyrosine into dopamine. TH-immunostaining enabled the identification of dopamine-containing neurons. Using this stain, a TH-positive neuron, implied the region’s dopamine production. A global analysis of their study yielded data confirming a mean reduction of 64% in the total dopamine count in individuals with PD versus those without. Remarkably, within specific regions of the SNc complex, the extent of cell loss differed vastly. The differentiation of cell loss in various midbrain areas is illustrated along a colorimetric scale (Figure 2). The median loss in the substantia nigra pars compacta was 86%, while a statistically insignificant loss was observed in the substantia nigra par lateralis (Damier et al. 1999).
Recently, synucleinopathies, which are the aggregation of the protein α-synuclein in the SNc, have been associated with neurodegeneration. α-Synuclein is an amino acid protein that is concentrated in nerve terminals (Goedert and Spillantini 2016). Bilateral injection of α-synuclein in the dorsal striatum region of a rat model has resulted in significantly reduced dopaminergic terminals present in the substantia nigra pars compacta. Moreover, α-synuclein injection also resulted in a mild loss of motor function in rats, with some latency for movement after six weeks (Tozzi et al. 2021). These studies suggest that there is an underlying mechanism behind the accumulation of α-synuclein in the SNc that may result in the loss of dopamine density and its subsequent dysfunction in PD.
Figure 2. A colorimetric scale of regional and loss of dopamine-containing neurons from the nigral complex as a result of Parkinson’s disease.
This figure illustrates neuronal loss in different parts of the midbrain. These values were quantified by comparing the mean numbers of TH-positive neurons in each group of five midbrains that elicited Parkinson’s disease with the means for five control midbrains (Damier et al. 1999). Regions of the midbrain most affected (90-100% cell loss) by neuron degradation are the Nigrosomes, designated by N in the upper portion of the figure. From “The substantia nigra of the human brain: II. Patterns of loss of dopamine-containing neurons in Parkinson's disease,” by Damier et al. 1999, Brain, 122(8), 1437-1448. Copyright 1999 by Oxford University Press. Adapted with permission.
Findings by Damier et al. (1999) indicates a pattern of cell loss and brain degeneration associated with Parkinson’s disease. Moreover, these patterns may include deviations or complexities of cell loss that differ within different midbrain regions.
Medicinal treatments of PD and the challenges of addressing dopamine depletion
Dopaminergic depletion catalyzes the development of Parkinson’s disease, specifically, the manifestation of motor symptoms that inhibit voluntary orderly movement of the human body. To treat these dopaminergic depletions, a common form of therapy is Dopamine replacement therapy (DRT), whereby the depletion of the body’s natural dopamine stores are replenished (Decourt et al. 2021).
Unfortunately, the development of dopamine dysregulation syndrome (DDS) is a potential side effect of DRT, leading to excessive use of dopaminergic medicine. While DDS is uncommon, with a prevalence estimated to be 3-4%, its potential avenue as a PD treatment is worth noting (Warren et al. 2017). Warren et al. (2017) sought to compile existing data that include iterations of DDS to accurately determine the prevalence of its side effects within the PD community. In a meta-analysis, they were able to identify 98 cases of DDS out of the 390 studies reviewed. The demographics of this review article indicated that approximately 82% of individuals with Parkinson’s that develop DDS are males with early-onset PD . Specific regions of the PD brain, specifically the ventral tegmental area and their projections to the ventral striatum and the nucleus accumbens, lack dopamine (Warren et al. 2017). This deficit may contribute to the development of DDS.
These regions have also been associated with reinforcement and addictive behaviors (Warren et al. 2017). As it relates to DDS, the sensitization of the ventral tegmental area promotes a response of incentive salience to dopamine replacement therapy. Incentive salience refers to the mechanism of wanting as a result of stimulation (Berridge 2017). In this case, incentive salience culminates in drug-seeking behavior due to dopamine replacement therapy. The challenge with treating PD with DRT is that it may result in DDS in a subset of affected individuals. Any signs of dopaminergic abuse would necessitate the identification of alternative therapies.
In addition to dopamine replacement therapy, the use of cell therapy has been explored. Cell therapy involves the viral restoration of dopamine lost to PD through the transplantation of midbrain dopamine (mDA). More specifically, homotopic grafts, which are the transplantation of a subject’s own tissue to a different location on the body, are capable of restoring mDA fiber density, forebrain innervation, dopamine levels and motor function in a rodent model (Moriarty et al. 2022). While this method of restoration shows potential in regenerating dopamine and motor function, clinical applications of this practice are still in their early stages. The use of cell therapy to treat PD has been presented with a few challenges. Given their heterogeneity and varying degrees of cell fate potential, the proportion of successfully transplanted mDA is often low, leading to unsuccessful regeneration of dopamine stores. In addition to the low percentage of restored mDA neurons and cellular heterogeneity, the cellular makeup of all grafts, whether homotopic or ectopic, have yet to be characterized. This lack of information leaves some uncertainties about the application of this treatment in a clinical setting (Xu et al. 2021). Therefore, further investigation is needed to confirm the potential of homotopic graft as a treatment strategy for PD.
Additional methods of mediating motor and non-motor symptoms of Parkinson’s disease
Although there is currently no cure for PD, medicines and other therapies can be used to alleviate some of the symptoms. DRT is one of the most common PD treatments that works by circumventing dopamine depletion and hence alleviating related motor symptoms . However, this therapy suffers from unwanted off-target effects such as dopamine dysregulation syndrome, dyskinesias and motor fluctuations (Warren et al. 2017).
Levodopa, a precursor to dopamine, is another class of drug that is deemed one of the most potent medications for PD first introduced in 1961. Despite its beneficial effects, some PD patients have developed progressive resistance to this drug, resulting in treatment failure over time. The use of Levodopa has also caused extrapyramidal side effects, including nausea and vomiting. For this, Levodopa is now administered in combination with carbidopa, which prevents its breakdown in the bloodstream and reduces certain side effects (Hauser et al. 2013).
Gemfibrozil, a Food and Drug Administration-approved lipid-lowering drug, is another medication with the potential to enact the same effects of DRT, but with potentially fewer side effects. This drug has so far only been tested on a mouse model of PD. To test the efficacy of Gemfibrozil at protecting dopamine neurons from degeneration, Gottschalk et al. (2021) tracked the disease progression of Gemfibrozil-treated PD mice. Their results demonstrated that Gemfibrozil protected TH-positive nigral dopaminergic neurons and TH-positive striatal fibers from the toxicity of the mouse model’s PD equivalent. In addition, Gemfibrozil also restored the presence of neurotransmitters where they were previously depleted as a result of PD and hence improved behavioral functionality in mice with PD. These findings suggest that Gemfiborzil may have therapeutic potential in the amelioration of PD in humans.
For over two decades, Toledo-Arral and his team have studied the anti-Parkinsonian benefits of intrastriatal carotid body (CB) transplants as a potential treatment option for PD. They investigated PD amelioration via the nigrostriatal dopaminergic pathway by monitoring the long-term functional recovery of Parkinsonian rats after receiving grafts of carotid body (CB) cell aggregates (Toledo-Aral et al. 2003). The carotid body is an organ that lies at the bifurcation of the carotid artery (Mínguez-Castellanos et al. 2008). Toledo-Aral et al. (2003) established that CBs contain dopaminergic glomus cells that are responsible for dopamine release as a consequence of hypoxia. They found that CB cell aggregates were able to induce functional recovery in Parkinsonian rats, and consistent with results from other laboratories, proved the feasibility and safety of the therapy in humans (Honda 1992; Luquin et al. 1999; Arjona et al. 2003).
Toledo-Aral et al. (2003) found that six out of twelve hemiparkinsonian (denoting the onset of asymmetric onset of PD, more prominent on one side of the body) rats that received CB grafts achieved a near-complete and stable recovery of their motor asymmetry after fifteen months of recovery. In these same rats, they found a marked improvement in TH-positive cell count and striatal dopaminergic replenishment (Toledo-Aral et al. 2003). Following the low success rates of CB transplantation in human PD patients, the group moved beyond CB graft transplantation to utilizing methods of in vitro-generated carotid body dopaminergic CB glomus cells. They found that stem-cell-derived CB glomus cells could be used as an additional form of regenerative PD therapy (Villadiego et al. 2023).
However, rats that received grafts exemplified sustained dopaminergic neuronal loss and striatal denervation. Hence, their study demonstrated both the potential benefits of surgical transplantation of carotid bodies and its potential failure. Better approaches will be needed to improve the clinical outcome of CB transplantation.
Conclusion
Parkinson’s disease (PD) is a complex and multifactorial disease. At its root, dopamine depletion, specifically in the substantia nigra pars compacta, is culpable for many of PD’s symptoms such as tremors, bradykinesia and dyskinesia. However, treatment options such as dopamine replacement therapy, Gemfibrozil and carotid body transplantation, have the potential to ameliorate PD symptoms, especially those caused by dopaminergic depletion in the brain. Although motor symptoms are the most apparent effects of Parkinson’s disease, non-motor symptoms such as cognitive decline and neuroendocrine abnormalities have the potential to wreak just as much havoc upon the individuals affected by the disease. Increasing evidence pointed to the fact that motor symptoms may have a strong association with specific non-motor symptoms, adding more complexity to the heterogeneity of Parkinson’s disease. Among the non-motor symptoms that accompany PD’s hallmark motor symptoms are neuroendocrine abnormalities.
While the pathophysiology of Parkinson’s disease is well understood today, future research directions should aim at improving existing treatment modalities or developing novel strategies to achieve beneficial clinical outcomes with minimal adverse effects.
Acknowledgements
We thank Dr. Kristel Tjandra for her assistance and direction throughout the writing of this review.
References
Arjona, V., Mínguez-Castellanos, A., Montoro, R. J., Ortega, A., Escamilla, F., Toledo-Aral, J. J., Pardal, R., Méndez-Ferrer, S., Martín, J. M., Pérez, M., Katati, M. J., Valencia, E., García, T., & López-Barneo, J. (2003) ‘Autotransplantation of human carotid body cell aggregates for treatment of Parkinson’s disease’, Neurosurgery, 53(2), 321–328, available: https://doi.org/10.1227/01.neu.0000073315.88827.72.
Berridge, K. C. (2017). ‘Incentive motivation and incentive salience’,. Reference Module in Neuroscience and Biobehavioral Psychology (pp. 100-104), Elsevier, available: https://doi.org/10.1016/b978-0-12-809324-5.00342-4.
Damier, P., Hirsch, E. C., Agid, Y., & Graybiel, A. M. (1999) ‘The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson’s disease’, Brain: A Journal of Neurology, 122(8), 1437–1448, available: https://doi.org/10.1093/brain/122.8.1437.
Decourt, M., Jiménez-Urbieta, H., Benoit-Marand, M., & Fernagut, P.-O. (2021) ‘Neuropsychiatric and Cognitive Deficits in Parkinson’s Disease and Their Modeling in Rodents’, Biomedicines, 9(6), 684, available: https://doi.org/10.3390/biomedicines9060684.
Drui, G., Carnicella, S., Carcenac, C., Favier, M., Bertrand, A., Boulet, S., & Savasta, M. (2014) ‘Loss of dopaminergic nigrostriatal neurons accounts for the motivational and affective deficits in Parkinson’s disease’, Molecular Psychiatry, 19(3), 358–367, available: https://doi.org/10.1038/mp.2013.3.
Gottschalk, C. G., Jana, M., Roy, A., Patel, D. R., & Pahan, K. (2021) ‘Gemfibrozil Protects Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease via PPARα-Dependent Astrocytic GDNF Pathway’, Journal of Neuroscience, 41(10), 2287–2300, available: https://doi.org/10.1523/JNEUROSCI.3018-19.2021.
Hauser, R. A., Hsu, A., Kell, S., Espay, A. J., Sethi, K., Stacy, M., Ondo, W., O'Connell, M., Gupta, S., (2013) ‘Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial’, The Lancet, Neurology, 12(4), 346– 356, available: https://doi.org/10.1016/S1474-4422(13)70025-5.
Honda, Y. (1992) ‘Respiratory and circulatory activities in carotid body-resected humans’, Journal of Applied Physiology, 73(1), 1–8, available: https://doi.org/10.1152/jappl.1992.73.1.1.
Kalaitzakis, M. E., Gentleman, S. M., & Pearce, R. K. B. (2013) ‘Disturbed sleep in Parkinson’s disease: Anatomical and pathological correlates’, Neuropathology and Applied Neurobiology, 39(6), 644–653, available: https://doi.org/10.1111/nan.12024.
Kehagia A.A., Barker R.A., Robbins, T.W. (2013) ‘Cognitive impairment in Parkinson's disease: the dual syndrome hypothesis’, Neurodegenerative diseases (2), 79-92, available: https://doi: 10.1159/000341998.
Kwon, K.-Y., Park, S., Kim, R. O., Lee, E. J., & Lee, M. (2022) ‘Associations of cognitive dysfunction with motor and non-motor symptoms in patients with de novo Parkinson’s disease’, Scientific Reports, 12, 11461, available: https://doi.org/10.1038/s41598-022-15630-8.
Leng, Y., Goldman, S. M., Cawthon, P. M., Stone, K. L., Ancoli-Israel, S., & Yaffe, K. (2018) ‘Excessive daytime sleepiness, objective napping and 11-year risk of Parkinson’s disease in older men’, International Journal of Epidemiology, 47(5), 1679–1686, available: https://doi.org/10.1093/ije/dyy098.
Luquin, M. R., Montoro, R. J., Guillén, J., Saldise, L., Insausti, R., Del Río, J., & López-Barneo, J. (1999) ‘Recovery of chronic parkinsonian monkeys by autotransplants of carotid body cell aggregates into putamen’, Neuron, 22(4), 743–750, available: https://doi.org/10.1016/s0896-6273(00)80733-3.
Lynch, D., Henihan, A.M., Kwapinski, W., Zhang, L. and Leahy, J.J. (2013) ‘Ash agglomeration and deposition during combustion of poultry litter in a bubbling fluidizedbed combustor’, Energy & Fuels, 27(8), 4684-4694, available: http://dx.doi.org/10.1021/ef400744u.
Mínguez-Castellanos, A., Escamilla-Sevilla, F., Méndez-Ferrer, S., Villadiego, J., Toledo-Aral, J., & López-Barneo, J. (2008) ‘Carotid body cell therapy for Parkinson’s disease’. In Gurutz Lina Zasoro, Fabio Cavaliere (Eds.), Current Situation and Future Prospects of Regenerative Medicine in Parkinson’s Disease (pp.63-72). Transworld Research Network. Available: https://doi.org/10.13140/2.1.2051.2962.
Moriarty, N., Gantner, C. W., Hunt, C. P. J., Ermine, C. M., Frausin, S., Viventi, S., Ovchinnikov, D. A., Kirik, D., Parish, C. L., & Thompson, L. H. (2022) ‘A combined cell and gene therapy approach for homotopic reconstruction of midbrain dopamine pathways using human pluripotent stem cells’, Cell Stem Cell, 29(3), 434-448.e5, available: https://doi.org/10.1016/j.stem.2022.01.013.
Pablo-Fernández, E. D., Breen, D. P., Bouloux, P. M., Barker, R. A., Foltynie, T., & Warner, T. T. (2017) ‘Neuroendocrine abnormalities in Parkinson’s disease’, Journal of Neurology, Neurosurgery & Psychiatry, 88(2), 176–185, available: https://doi.org/10.1136/jnnp-2016-314601.
Posavi, M., Diaz-Ortiz, M., Liu, B., Swanson, C. R., Skrinak, R. T., Hernandez-Con, P., Amado, D. A., Fullard, M., Rick, J., Siderowf, A., Weintraub, D., McCluskey, L., Trojanowski, J. Q., Dewey, R. B., Huang, X., & Chen-Plotkin, A.S. (2019) ‘Characterization of Parkinson’s disease using blood-based biomarkers: A multicohort proteomic analysis’, PLoS Medicine, 16(10), e1002931, available: https://doi.org/10.1371/journal.pmed.1002931.
Sakuta, H., Suzuki, K., Miyamoto, T., Miyamoto, M., Numao, A., Fujita, H., Watanabe, Y., & Hirata, K. (2016) ‘Serum uric acid levels in Parkinson’s disease and related disorders’, Brain and Behavior, 7(1), e00598. available: https://doi.org/10.1002/brb3.598.
Smith, Y., & Masilamoni, J. G. (2010). Substantia Nigra. In K. Kompoliti & L. V. Metman (Eds.), Encyclopedia of Movement Disorders (pp. 189–192). Academic Press. available: https://doi.org/10.1016/B978-0-12-374105-9.00288-4.
Spillantini, M.G. and Goedert, M. (2016) ‘Synucleinopathies: past, present and future’, Neuropathol Appl Neurobiol, 42: 3-5. available: https://doi.org/10.1111/nan.12311.
Tod, A. M., Kennedy, F., Stocks, A.J., McDonnell, A., Ramaswamy, B., Wood, B., & Whitfield, M. (2016) ‘Good-quality social care for people with Parkinson’s disease: A qualitative study’, BMJ Open, 6(2), e006813. available: https://doi.org/10.1136/bmjopen-2014-006813.
Toledo-Aral, J. J., Méndez-Ferrer, S., Pardal, R., Echevarrıa, M., & López-Barneo, J. (2003) ‘Trophic Restoration of the Nigrostriatal Dopaminergic Pathway in Long-Term Carotid Body-Grafted Parkinsonian Rats’, The Journal of Neuroscience, 23(1), 141–148, available: https://doi.org/10.1523/JNEUROSCI.23-01-00141.2003.
Tozzi, A., Sciaccaluga, M., Loffredo, V., Megaro, A., Ledonne, A., Cardinale, A., Federici, M., Bellingacci, L., Paciotti, S., Ferrari, E., La Rocca, A., Martini, A., Mercuri, N. B., Gardoni, F., Picconi, B., Ghiglieri, V., De Leonibus, E., & Calabresi, P. (2021) ‘Dopamine-dependent early synaptic and motor dysfunctions induced by α-synuclein in the nigrostriatal circuit’, Brain, 144(11), 3477–3491, available: https://doi.org/10.1093/brain/awab242.
Trist, B. G., Hare, D. J., & Double, K. L. (2019) ‘Oxidative stress in the aging substantia nigra and the etiology of Parkinson’s disease’, Aging Cell, 18(6), e13031. available: https://doi.org/10.1111/acel.13031.
Urso, D., van Wamelen, D. J., Batzu, L., Leta, V., Staunton, J., Pineda-Pardo, J. A., Logroscino, G., Sharma, J., & Ray Chaudhuri, K. (2022) ‘Clinical trajectories and biomarkers for weight variability in early Parkinson’s disease’, NPJ Parkinson’s Disease(8), 95, available: https://doi.org/10.1038/s41531-022-00362-3.
Voruz, P., Constantin, I. M., & Péron, J. A. (2022) ‘Biomarkers and non-motor symptoms as a function of motor symptom asymmetry in early Parkinson’s disease’, Neuropsychologia, 177, 108419, available: https://doi.org/10.1016/j.neuropsychologia.2022.108419.
Villadiego, J., Muñoz-Manchado, A. B., Sobrino, V., Bonilla-Henao, V., Suárez-Luna, N., Ortega-Sáenz, P., Pardal, R., López-Barneo, J., & Toledo-Aral, J. J. (2023) ‘Protection and Repair of the Nigrostriatal Pathway with Stem-Cell-Derived Carotid Body Glomus Cell Transplants in Chronic MPTP Parkinsonian Model’, International Journal of Molecular Sciences, 24(6), 5575, available: https://doi.org/10.3390/ijms24065575.
Warren, N., O’Gorman, C., Lehn, A., & Siskind, D. (2017) ‘Dopamine dysregulation syndrome in Parkinson’s disease: A systematic review of published cases’, Journal of Neurology, Neurosurgery & Psychiatry, 88(12), 1060–1064, available: https://doi.org/10.1136/jnnp-2017-315985.
Wojtala, J., Heber, I. A., Neuser, P., Heller, J., Kalbe, E., Rehberg, S. P., Storch, A., Linse, K., Schneider, C., Gräber, S., Berg, D., Dams, J., Balzer-Geldsetzer, M., Hilker-Roggendorf, R., Oberschmids, C., Baudrexel, S., Witt, K., Schmidt, N., Deuschl, G., & Reetz, K. (2019) ‘Cognitive decline in Parkinson’s disease: The impact of the motor phenotype on cognition’, Journal of Neurology, Neurosurgery & Psychiatry, 90(2), 171–179. available: https://doi.org/10.1136/jnnp-2018-319008.
Xu, P., He, H., Gao, Q., Zhou, Y., Wu, Z., Zhang, X., Sun, L., Hu, G., Guan, Q., You, Z., Zhang, X., Zheng, W., Xiong, M., & Chen, Y. (2022) ‘Human midbrain dopaminergic neuronal differentiation markers predict cell therapy outcomes in a Parkinson’s disease model’, The Journal of Clinical Investigation, 132(14), e156768. available: https://doi.org/10.1172/JCI156768.
Yang, W., Hamilton, J. L., Kopil, C., Beck, J. C., Tanner, C. M., Albin, R. L., Ray Dorsey, E., Dahodwala, N., Cintina, I., Hogan, P., & Thompson, T. (2020) ‘Current and projected future economic burden of Parkinson’s disease in the U.S.’, NPJ Parkinson’s Disease, 6(15). available: https://doi.org/10.1038/s41531-020-0117-1
Yang, Q., Nanivadekar, S., Taylor, P. A., Dou, Z., Lungu, C. I., & Horovitz, S. G. (2021) ‘Executive function network’s white matter alterations relate to Parkinson’s disease motor phenotype’, Neuroscience Letters, 741, 135486. available: https://doi.org/10.1016/j.neulet.2020.135486.