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Parkinson's Disease: The Brain At Odds With Itself

"With Parkinson's, it's like you're in the middle of the street and you're stuck there in cement shoes and you know a bus is coming at you, but you don't know when. You think you can hear it rumbling, but you have a lot of time to think. And so you just don't live that moment of the bus hitting you until it happens. There's all kinds of room in that space" by Michael J. Fox.

Neurological diseases have become a leading cause of disabilities worldwide. Parkinson's disease (PD) is the fastest growing and second most common neurological disease globally, second to Alzheimer's disease. PD is a neurodegenerative disease that predominantly affects the motor regions of the central nervous system. Clinically, it is typically recognized by a trio of motor symptoms, including tremors, stiffness, and bradykinesia, the latter of which is defined by a slowing of both movement and pace (Kalia & Lang, 2015). Being diagnosed with Parkinson's disease is a turning point in one's life. Not only is it an incurable condition that necessitates long-term medication to control symptoms, but it also carries with it a slew of obstacles as simple motions become increasingly challenging over time, eventually interfering with routine daily chores (Kouli et al., 2018). Moreover, the disease's advancement frequently culminates in dementia. While PD has been a rare condition for much of history, its prevalence has nearly doubled since the 1990s and 2015, with an estimated 6.2 million people currently living with it (Feigin et al., 2017). In addition, the burden of disease is anticipated to increase to nearly 17 million by 2040 due to population aging, longer life expectancy and industrialization (Dorsey et al., 2018). This underscores the need of a call to action to tackle PD.

Figure 1 - As Parkinson's disease progresses, many patients develop dementia and memory loss (Krause, 2022).

Parkinson's Disease: Dopamine Deficiency and Erroneous Brain Instructions

According to Tinbergen (2020), the mammalian brain evolved to support naturalistic activities that allow us to interact with our environment, such as decision-making and locomotion. Triggered by the intention to move, voluntary movements are carried out consciously under the command of the brain. Intention is communicated to the muscles via brain impulses that travel through networks of neurons (nerve cells), which subsequently apply pressure and displacements that impact our surroundings (Schwartz, 2016). Motor neurons, also known as efferent neurons, are responsible for conveying impulses from the central nervous system to the muscles in order to initiate movement. Motor neurons do this by releasing neurotransmitters, which are chemical messengers that transport signals (messages) from one neuron to the next target cell (which might be another neuron, a muscle cell, or a gland), prompting reactions that result in muscle movement (Zayia & Tadi, 2023). Dopamine-producing (dopaminergic) neurons located in the substantia nigra, a region in the brain's basal ganglia that plays a significant role in reward and movement, are one such crucial collection of neurons (Triarhou, 2002).


Dopamine is a neurotransmitter that governs numerous processes, including physical movement, memory and cognition, sleep-wake cycles, and emotions such as depression and mania. Parkinson's disease is caused by the loss or degeneration of dopaminergic neurons. This causes the circuits in the basal ganglia to misfire. Along with the cerebellum, the basal ganglia acts as a sort of advisor, assisting individuals in acquiring adaptive skills through classical conditioning, i.e., rewarding successful attempts with dopamine surges and punishing failures with dopamine release restrictions (Palfreman, 2015). When dopamine synthesis is interrupted, as in Parkinson's disease, the signals processed by the basal ganglia become scattered, and the brain delivers incorrect directives. Damaged signals are sent to other parts of the brain, including the thalamus (which carries both motor and sensory information) and the cortex (which is in charge of many higher-level processes including language and awareness) (Wu et al., 2020). These erroneous impulses disrupt the brain-muscle relationship. One of the reasons people with Parkinson's disease struggle to grasp tiny things and move about is because their motions are hesitant, rigid, unsteady, and untimely. These are symptoms of a brain at battle with itself.

Figure 2 - Cognitive impairment in Parkinson's disease can lead to distraction and confusion (Brody, 2015).

Dopamine insufficiency causes the clinically recognized triad of motor symptoms (parkinsonism), which frequently emerge gradually and worsen with time. This trio comprises bradykinesia (slow motions and speed), tremors, and rigidity (Albin et al., 1989; Triarhou, 1997). However, it is well acknowledged that Parkinson's disease is also linked with a variety of non-motor symptoms that are present in the great majority of patients and may even predate the onset of motor symptoms. The spectrum of these non-motor symptoms is quite broad and includes autonomic disorders (related to the autonomic nervous system that controls involuntary actions such as heartbeat and blood vessel dilation or constriction), sensory deficits with decreased sense of touch and smell, sleep disorders, and neuropsychiatric disorders such as depression, dementia, and hallucinations. Patients may also experience mood swings, fatigue, depression, and memory problems (Löhle et al., 2009; Micieli et al., 2003). These non-motor symptoms should be considered by physicians, not only because they have a significant impact on the health-related quality of life of PD patients, but also because they often precede the onset of motor symptoms.


Alpha-synuclein: The Hallmark of Parkinson’s Disease

Since the discovery of dopamine as a neurotransmitter in the 1950s, research on Parkinson's disease has yielded a comprehensive body of evidence revealing that this is an age-related, multifactorial ailment influenced by both inherited and environmental factors. Despite the fact that this condition is not hereditary, it is now recognized that carrying specific genes increases susceptibility to the disease. Aside from genetics, exposure to specific substances and various lifestyle factors also raise the likelihood of developing it (Warner & Schapira, 2003). The fundamental mechanism underlying the loss of dopamine-producing neurons in PD was not unveiled until 1997. The missing piece of the Parkinson's jigsaw was a protein known as alpha-synuclein. Lawrence Golbe, a neurologist in New Jersey, recognized the significance of such molecule in Parkinson's disease after examining two patients who were descendants of a large family from the Italian hamlet of Contursi. This family had an exceptionally rare genetic form of PD, with a 50% probability of developing it. Further analysis revealed that those affected had a defective gene on chromosome 4 which coded for alpha-synuclein (Palfreman, 2015).

Figure 3 - The journey to Parkinson involves the aggregation of alpha-synuclein protein (Sharma, 2023).

Alpha-synuclein occurs naturally in the nervous system, being universally expressed throughout the brain. Under physiological conditions, alpha-synuclein exists in a delicate balance between soluble and membrane-bound conditions. However, healthy and functional alpha-synuclein proteins can occasionally malfunction due to genetic mutations, environmental factors, or aging. Like amyloid protein which misfolds and accumulates in the brain of Alzheimer's patients, alpha-synuclein can change conformation, misfold, and clump together, damaging neurons (especially dopamine-producing neurons). In Parkinson's patients, this abnormal aggregation or clumping of alpha-synuclein protein takes the form of Lewis bodies, which cannot be destroyed by the body and therefore spread and damage brain cells (Gomperts, 2016; Xu & Pu, 2016). Although Parkinson's disease is rarely inherited in this way, the discovery of alpha-synuclein provided significant insight into the key molecular mechanisms underlying the disease. Although the majority of PD patients do not carry this mutation, postmortem testing found sticky deposits of alpha-synuclein in their brains.


Parkinson’s Disease Management: Challenges and Pitfalls

Parkinson's disease is an incurable disorder with no proven disease-modifying drug, i.e. treatment that delays or slows its progression by targeting the underlying cause. Non-pharmacologic therapies (such as exercise and physical, occupational, and speech therapy) and pharmacological approaches (typically employing levopoda, a dopamine precursor) can help decrease symptoms and enhance patients' quality of life (Fox et al., 2018). Pharmacological therapies attempt to increase levels of dopamine in the brain, but often comprise compounds that are either precursors or substitutes for dopamine. This is because dopamine cannot cross the blood-brain barrier and go directly into the brain. Levopoda, on the other hand, can cross the blood-brain barrier and access the brain, where it is converted into dopamine. Levodopa is often coupled with carbidopa (Lodosyn), which prevents the early conversion of levodopa to dopamine outside the brain (Pinder, 1970). This is critical not just for preventing or reducing adverse effects, but also for ensuring therapeutic efficacy. However, due to the diversity of motor and non-motor characteristics in Parkinson's patients, there is an urgent need to develop tailored and targeted therapies (Kobylecki, 2020). Alternatively, surgical techniques such as deep brain stimulation, in which electrodes are surgically implanted in a specific region of the brain, may be considered in individuals who have severe disease or are refractory to levodopa. These electrodes are connected via a subcutaneous wire to a neurostimulator, a pacemaker-like device, implanted near the clavicle that transmits electrical impulses to the brain and can alleviate illness symptoms (Starr et al., 1998).

Figure 4 - Deep brain stimulation is highly effective in relieving the motor symptoms of Parkinson's disease (Harnish, 2022).

Precise diagnosis remains a key challenge in Parkinson's management, as clinical aspects of the disease often overlap with other neurodegenerative diseases and diagnostic methods or biomarkers do not yet allow definitive diagnosis in the early stages. While Parkinson's disease can be easily diagnosed by clinical examination in patients with a classic medical history and asymmetric motor symptoms, and no atypical symptoms, Parkinson's disease often goes unrecognized, with an error rate of 15% to 24% in routine clinical practice (Rajput & Rajput, 2014; Schrag, 2002). This is due to the fact that Parkinson's disease is diagnosed based on the patient's medical history and neurological examination. Prodromal features, or early signs of disease that appear before the onset of serious disease symptoms (rapid eye movements, trouble sleeping, constipation), obvious movement problems (tremors, stiffness, slowness), and psychological or cognitive problems (cognitive decline, depression, anxiety) are among the data documented in the medical history of a Parkinson's patient (Tolosa et al., 2021).


Biomarkers for Parkinson's Diagnosis: A New Hope in the Horizon

Finding a reliable diagnosis for Parkinson's disease has been a major challenge, and identifying the earliest stages of the disease is still an urgent unmet need. However, the approach to diagnosing Parkinson's disease is shifting from clinical to biomarker-based, enabling for earlier identification, detection of distinct subtypes with differing prognoses, and the development of novel disease-modifying drugs (Tolosa et al., 2021). For a biomarker to revolutionize the treatment of Parkinson's disease, three requirements must be met. First, it must be extremely sensitive and specific, able to distinguish Parkinson's disease from other neurodegenerative diseases. Second, to detect Parkinson's disease in its early stages, especially in the prodromal phase. Third, changes in the natural course of the disease over time or as a result of targeted therapy must be easy to monitor, affordable, and accurate. Remarkably, a new era of biomarker and therapeutic discovery for Parkinson's disease is now underway (Klein & Bloem, 2023).

Figure 5 - A new era of Parkinson's diagnosis discovery is now underway, bringing new hope on the horizon (Cox, 2021).

The alpha-Synuclein Seed Amplification Assay has proven to be a tremendous leap forward in the understanding and diagnosis of Parkinson's disease. This new tool skilfully exploits a pathological feature of abnormal alpha-synuclein: its ability to move through connected neuronal networks and serve as a template to promote additional aggregation of healthy alpha-synuclein, which misfolds and clusters into seeds (Ma et al., 2019). This approach not only detects pathology in the cerebrospinal fluid of individuals previously diagnosed with Parkinson's disease, but also in individuals awaiting diagnosis and even in individuals who do not present clinical symptoms, but are at high risk of disease. This is due to the exceptional sensitivity of the assay in identifying aberrant alpha-synuclein: 93% of Parkinson's patients were accurately identified as having abnormal alpha-synuclein (Siderowf et al., 2023). The idea behind this approach is to treat spinal fluid samples with a fluorescent molecule that glows when clumps of alpha-synuclein form. The patient's spinal fluid sample is then seeded with healthy alpha-synuclein. If the sample contains aberrant alpha-synuclein, as in a Parkinson's patient, clumps will form and the dye will glow. By contrast, if there is no abnormal alpha-synuclein, the dye will not glow (Aman, 2022). The Syn-SAA approach therefore represents a game-changing biomarker in the early detection of Parkinson's disease. This is of the utmost importance as the brain is not extensively damaged in the early stages of the disease and can heal much faster, sometimes only with minor lifestyle changes. This biomarker can detect Parkinson's disease before it physically manifests, signaling a paradigm shift in Parkinson's diagnosis.


Conclusions

Affecting 2-3% of people over the age of 65, Parkinson's disease is the second most prevalent neurological condition in the world. Parkinson's disease is characterized by neuronal loss in the substantia nigra, which results in dopamine insufficiency, and intracellular inclusions containing alpha-synuclein aggregates (Lewy bodies). Although clinical diagnosis is based on the presence of bradykinesia and other cardinal motor characteristics, Parkinson's disease is associated with several non-motor symptoms that compound overall impairment and make diagnosis and therapy extremely challenging. Treatment of Parkinson's disease is anchored on the pharmacological substitution of dopamine, however drug options are limited and Levodopa is the cornerstone of treatment. While cutting-edge therapies have attempted to restore dopamine levels using gene- and cell-based approaches (targeted approaches), one of the major hurdles has been finding indicators of prodromal (early) disease states that would allow for earlier introduction of novel therapies. The discovery that alpha-synuclein can be used to diagnose Parkinson's disease represents a tremendous opportunity for the disease to evolve from a subjectively diagnosed condition to an objectively defined illness. This will pave the way for new paradigms of clinical care, such as earlier diagnosis and tailored therapies, as well as faster and cheaper drug development.


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