INTRODUCTION:

Parkinson's disease (PD) is a neurodegenerative condition brought on by the loss of a particular kind of neuron that is essential to the brain's dopamine synthesis¹. PD, which affects 0.2% of the world's population, is the second most common neurodegenerative illness. global population, 1% of those over 60, and as much as 4% of the total population more than 80 years old².

Parkinson's disease (PD) causes stiffness, tremor, rigidity, bradykinesia, and freezing cramps in the muscles. Parkinson's illness may pathologically result in Dopamine depletion in the brain as a result of intra Lewy bodies are inclusions in the cytoplasm. It's unclear why creation of Lewy bodies results in the death of neurons³. The idea that depression could be caused by characteristics unique to Parkinson's disease (PD) is reinforced by the observation that some brain abnormalities, such as monoaminergic deficiencies and lesions of frontal subcortical circuits, which are known to play a role in the etiology of PD, may also be linked to depression⁴.

Significant smell impairment is now known to be associated with early-stage Parkinson disease (PD), with a prevalence of almost 90% in cases of PD that occur sporadically⁵. The lengthy diagnosis process for Parkinson's disease is one of the primary barriers to slowing down the disease's progression. The most visible symptom, tremors, might manifest years after the disease first manifests. Indeed, a preclinical phase for Parkinson's disease (PD) has been hypothesized to last an average of 15 years¹.

Lewy bodies, intracytoplasmic inclusions, are one reason why Parkinson disease may result in dopamine depletion in the brain. The reason behind the loss of neurons due to Lewy body development remains unclear ³. Additionally, depression has a significant role in the poor health-related quality of life experienced by PD patients. It is linked to decreased functionality, cognitive impairment, and higher levels of stress among those who provide care for PD patients⁴.

In the United States, more than one million people have been diagnosed with Parkinson disease (PD), multiple sclerosis, amyotrophic lateral sclerosis, muscular dystrophy, and myasthenia gravis combined. Approximately 1 in 100 Americans over 60 suffer with Parkinson's disease (PD) ². Some brain alterations known to be involved in the pathogenesis of Parkinson's disease (PD) such as monoaminergic deficits and lesions of frontal-subcortical circuits may also be linked to depression, lending credence to the theory that PD-specific factors may contribute to depression⁴.

Historically, in clinical practice, the most common cause of Parkinsonism has been referred to as "idiopathic" Parkinson's disease (PD). However, the nosology of PD classification needs to be continually revaluated due to the discovery of monogenic forms of PD (which may be clinically indistinguishable from the "idiopathic" form), the clinical heterogeneity of the disease, and the clinical overlap between PD dementia, dementia with Lewy bodies, and other forms of Parkinsonism 2]. A major contributing factor to the poor health-related quality of life experienced by PD patients is depression, which is also linked to decreased functioning, cognitive decline, and higher stress levels in those who provide care for PD patients. Thus, it is essential to comprehend depression in PD patients in order to provide the best care possible for those who have this illness⁵.

The diverse array of nervous cells in the enteric nervous system (ENS) forms a highly organized and integrated network of plexuses rather than a mere collection of relay ganglia. This complex arrangement and functionality of the ENS have earned it the moniker "second brain," and the gastrointestinal (GI) tract has been described as a "neurological organ" as a result³.

PATHOPHYSIOLOGY:

The degeneration of dopaminergic neurons in the substantia nigra is a hallmark of Parkinson's disease. The Lewy body, primarily composed of α-synuclein protein aggregations, is a neuronal inclusion that is the pathologic characteristic of Parkinson's disease⁶. Numerous other motor and non-motor circuits are affected by the neuropathology, but dopaminergic neurons experience the fastest rate of neuronal death as a result of these disease mechanisms⁷.

Parkinson's disease is characterized by a problem of the extrapyramidal framework, which includes basal ganglia motor structures. The disease's clinical highlights are brought on by a decrease in motor activity and a subsequent loss of dopaminergic capacity8. This early pathology is linked to symptoms including reduced smell and rapid eye movement sleep behavior disorder, which cause people to physically act out their dreams while they sleep and lose their usual rapid eye movement sleep paralysis. Pathology advances to other midbrain and basal forebrain structures, including the substantia nigra pars compacta, in stages three and four⁶.

Patients in these early stages (Braak stages 1 and 2) are not yet exhibiting symptoms. The substantia nigra, in Braak stages 3 and 4, advances with the disease. The basal forebrain and midbrain become involved. Ultimately, In the neocortex, pathological alterations are visible ⁸.

Neuronal death is influenced by genetic mutations that code for central nervous system proteins. More specifically, aberrant self-aggregation of alpha-synuclein occurs. This insoluble, aggregated alpha-synuclein is a primary component of Lewy Bodies, which are inclusions in the cells that are indicative of PD⁶. One relatively recent discovery is that these pathological changes are accompanied by compensatory changes in brain activity in regions of the brain that are initially unaffected by the pathology of Parkinson's disease. These changes include recruitment of cortical regions that are less connected to the basal ganglia and a shift towards more anterior corticostriatal circuits⁷.

Aggregations of Parkinson disease proteins are linked to the demise of cells that produce dopamine. The cornerstone of treating Parkinson's disease is dopamine supplementation. But Parkinson's disease also affects other neurotransmitter systems, such as the norepinephrine, acetylcholine, and serotonin systems⁶.

The distribution of lewy bodies serves as the basis for this pathological stage. PD's pathological hallmark is a lewy body. They consist of many neurofilament and are asynuclein- immunoreactive inclusions. proteins in addition to those involved in proteolysis. Among them is ubiquitin, a heat shock protein that is crucial for function in directing the degradation of other proteins⁸.

Fig. 1: A brain without and with Parkinson's Disease compared in Substantia Nigra

Clinical Sign and Symptoms:

PD is a neurological condition that progresses over time. Bradykinesia, or slowing down of movement, postural instability, stiffness, and resting tremor are the four cardinal motor symptoms⁹. Moreover, freezing (motor blocks) and flexed posture have been identified as characteristic hallmarks of parkinsonism, the most prevalent type of which is Parkinson's disease (PD). Because people with Parkinson's disease (PD) have a variety of profiles and lifestyles, it is important to consider each patient's requirements and objectives while evaluating motor and nonmotor deficits¹⁰.

The motor symptoms of Parkinson's disease are the most recognizable and include tremors or shaking, especially in the hands, fingers, or arms, rigidity or stiffness in the arms, legs, or trunk, bradykinesia (slow movement) or akinesia (lack of movement), postural instability or balance problems, and difficulty with walking, including shuffling or freezing ¹¹.

One of the most defining characteristics of the illness is a resting tremor, which affects 70% of patients. Long-term absence of tremor during a patient's illness should prompt a careful consideration of other neurologic conditions that can manifest as signs of parkinsonism, though they are not necessary for diagnosis⁹. These conditions include progressive supranuclear palsy, corticobasal ganglionic degeneration, and multiple system atrophies.¹¹

There are four symptoms that the majority of patient’s experience:

a. Rigidity:

b. Resting tremor:

c. Bradykinesia:

d. Postural reflexes impairment:

A. Rigidity:

When a patient tries to move their arm, neck, or leg, they experience stiffness or freezing. The person experiences weakness and a lack of grace or pace while their muscles remain highly tense and contracted.

B. Tremor Reset:

When an individual is at rest and their muscles are relaxed, such as when they are hanging next to their trunk or placing their hands on their laps, this is known as the relaxed state. The illness primarily affects the fingers or hands and is more common in stressful environments.

C. Bradykinesia:

It is typified by a slowness or incapacity to start moving. Reduced facial movement, a shuffled walk, altered speech patterns, and issues with dexterity are among the contributing flaws. This is the most difficult part of the illness for many people, and they often feel extreme dissatisfaction. Even performing daily tasks like writing, dressing, eating, and serving with cutlery, as well as moving out of seats and beds, is difficult or impossible for the patient.

D. Impairment of Postural Reflexes:

The inability to balance the entire body with conditional coordination is known as postural instability. Patients may lean forward or backward to help with balance and fall more readily. This leaning is characterized by a rounded shoulder, a bowed head, and slight hip and knee flexion¹¹.

Stages of Parkinsons Disease:

Stage 1: Unilateral involvement; blank faces; affected arm in semi flexed position with tremor; patient leans to unaffected side¹².

Stage 2: Bilateral involvement with early postural changes; slow, shuffling gait with decreased excursion of legs ¹².

Stage 3: Pronounced gait disturbances and moderate generalized disability; balance is a major problem; severe tremor, rigidity, and/or brassiness¹².

Stages 4: Significant disability; limited ambulation with assistance¹².

Stages 5: Complete invalidism; patient confined to bed or chair; cannot stand or walk, even with assistance¹².

Diagnosis:

The clinical symptoms from the history and examination, along with the way the disease responds to dopamine drugs and the emergence of motor fluctuations, are used to diagnose Parkinson's disease¹³. Researchers have also looked into factors that indicate how quickly Parkinson's disease (PD) progresses, such as motor progression, placement in a nursing institution, and lower survival times¹⁵. Suchowersky and colleagues30 conducted an evidence-based review and found that stiffness, bradykinesia, onset age of PD, and reduced dopamine responsiveness were all predictive of faster motor progression in PD¹⁴.

Clinical Diagnostic Criteria:

The 2015 MDS criteria ought should be used to diagnose Parkinson's disease. Accurate diagnosis can be improved by a therapeutic response to levodopa medication. However, a longer course of the disease (≥ 5 years) improves diagnostic accuracy greatly; hence, long-term clinical follow-up is preferable to diagnosis based on responsiveness to levodopa medication at baseline¹⁶.

Diagnostic Imaging:

The early use of cranial magnetic resonance imaging (cMRI) in the differential diagnosis of Parkinson disorders is recommended. T1- and T2-weighted cMRI scans, ideally high- resolution 3D, should be used to evaluate the exclusion criteria for Parkinson's disease (PD). These scans may also include diffusion- and iron-sensitive/susceptibility-weighted sequences¹⁶.

Genetic Diagnostics:

Genetic diagnostics If the patient has two first-degree relatives with Parkinson's disease (PD) or one first-degree relative and one second-degree relative with PD, or if the disease manifests before the age of fifty, diagnostic genetic testing should be made available upon request¹⁶.

Diseases and Conditions That May Require Differentiation from Parkinson’s Disease Alzheimer’s disease:

· Basal ganglia tumor

· Benign essential tremor

· Cerebrovascular disease

· Corticobasal degeneration

· Creutzfeldt–Jakob disease

· Dementia with Lewy bodies

· Drug-induced parkinsonism

· Metabolic causes (e.g., hypoparathyroidism, thyroid dysfunction, nutritional deficiencies)

· Multiple-system atrophy

· Normal-pressure hydrocephalus

· Olfactory dysfunction

· Olivopontocerebellar atrophy

· Post-traumatic brain injury Parkinson’s disease

· Progressive supranuclear palsy

· Shy–Drager syndrome

· Subdural hematoma

· Wilson’s disease

The patient's history and physical examination are typically the only factors used to diagnose Parkinson's disease (PD), despite recent advancements in our understanding of the disease's processes¹⁵. The existence of a typical rest tremor raises the probability of pathologically supported Parkinson's disease (PD) more than any other single trait, albeit 20% of individuals do not develop a typical rest tremor¹⁴.

· Shaking or tremor

· Slowness of movement, called bradykinesia

· Stiffness or rigidity of the arms, legs or trunk

· Trouble with balance and possible falls, also called postural instability¹⁷.

Surgical Treatments:

Future treatment for Parkinson's disease (PD) may involve cell transplantation. Both autologous and non-autologous cells have been used in experiments. Among the cells used in this transplantation research are induced pluripotent stem cells and human embryonic stem cells¹⁷. DBS, which uses implanted pulse generators, has essentially superseded conservative surgical techniques such stereotactic removal of physiologically determined hyperactive brain centers (thalamotomy, pallidotomy)¹⁸.

When levodopa is responsive in treating motor symptoms but motor fluctuations and dyskinesias become incapacitating, surgery is the recommended course of action¹⁹. Further research has attempted to determine whether the grafted dopaminergic neurons will live and form connections in the brain, whether the patient's brain can harmonize and make use of the grafted neurons, and whether the grafts can result in a significant clinical improvement since the first clinical trial involving the transplantation of dopaminergic- neuron-rich human fetal mesencephalic tissue into the striatums of PD patients in 1987¹⁷.

Deep Brain Stimulation:

Many patients with moderate-to-advanced disease have poor quality of life despite receiving optimal pharmacological therapy because of symptoms such as levodopa-unresponsiveness, dyskinesia that causes problems, or fluctuating response. DBS employing implanted pulse generators has essentially superseded conservative surgical techniques such as stereotactic removal of physiologically defined hyperactive brain nuclei (thalamotomy, pallidotomy)¹⁸.

Focused Ultrasound:

Some patients have found benefit with unilateral focused ultrasound lesioning of the STN or thalamus (in tremor-dominant forms of Parkinson's disease), especially if their symptoms are noticeably asymmetric.89 Finally, patients with Parkinson's disease who are most affected by their gait issue are increasingly being investigated for spinal cord stimulation¹⁸.

Treatments Using Replacement Cells:

Previous PD stem cell transplantation have had varying degrees of success. Despite strong graft survival, several transplant patients experienced "off" dyskinesias, despite the fact that some of them initially improved¹⁸.

Medical Therapies:

PD patients, medical therapy is the cornerstone of care. Pharmacotherapy and no pharmacological alternative methods including education, exercise, speech treatment, support groups, and diet are among them. The patient's age, illness stage, concerning symptoms, and the benefit/risk ratios of various medicines all influence the therapeutic approaches²⁰. Patient and family/caregiver education is important but critically needed in a chronic progressive neurologic disease. Key to success is balancing need to know versus readiness to absorb potentially disturbing data. Some programs have been developed which delineate topics necessary for specific neurologic conditions like PD²¹.

Levodopa:

The most effective drug for treating Parkinson's disease (PD) motor symptoms is levodopa. It is widely and swiftly digested, with a short half-life of around 1.5 hours. In the proximal small intestine, levodopa is avidly absorbed and subsequently processed by aromatic L-amino acid decarboxylase (AADC)²¹.

Agonists for Dopamine:

The way that dopamine agonists (DA) work is by activating dopaminergic receptors. The agonists that are currently in use are derivatives of non-ergot, specifically apomorphine, rotigotine, pramipexole, and ropinirole ²¹.

Inhibitors of catechol-o-methyltransferase (COMT):

COMT metabolizes levodopa both centrally and peripherally. As a result, COMT inhibitors help levodopa work longer and are helpful when used in conjunction with it to address "off" periods. With every dose of levodopa, 200 mg of entacapone are administered²¹.

Inhibitors of monoamine Oxidase-B (MAO-B):

A common mitochondrial enzyme called monoamine oxidase catalyzes the oxidative deamination of several different monoamines. It exists in the MAO-A and MAO-B isoforms. Whereas MAO-B has an affinity for beta-phenylethylamine, MAO-A has a stronger affinity for noradrenaline and serotonin²¹.

Surgical Therapies:

Patients with Parkinson's disease (PD) who are gradually losing response to conventional dopamine therapy are typically candidates for surgical therapy. Particularly, persistent motor fluctuations and uncontrollable choreic or dystonic movements, or dyskinesias, may be signs of eligibility²⁰.

Stimulating The Deep Brain (DBS):

In DBS, leads are surgically inserted into the globus pallidus interna (GPi) or subthalamic nucleus (STN), either unilaterally or bilaterally. An implantable pulse generator (IPG), which is typically positioned in the chest, is then attached to these leads. Although the precise mode of action is unknown, the cortico-basal ganglia network's pathogenic firing patterns are believed to be modulated²⁰.

Enteral gel Levofloxacinopa (LCIG):

Percutaneous endoscopic gastrostomy using a jejunal extension tube (PEG-J) is the method used to give LCIG. Small dosages of levodopa/carbidopa are given to the small intestine approximately once every minute via an external pump. Levodopa is supplied in steady amounts by LCIG all day long²⁰.

Ultrasound with Focus (FUS):

FUS uses accurate, incision-free transcranial acoustic energy delivery. Patients are positioned within a stereotactic head frame that is connected to an ultrasonic transducer that is compatible with MRIs²⁰.

Experimental Therapies:

While the majority of modern PD therapy is medical (pharmacological), certain PD patients may benefit from surgical therapy (such as deep brain stimulation), but some investigational therapies provide hope and a potential course of treatment. These include gene therapy, strong light therapy for sleep difficulties connected to Parkinson's disease, and stem-cell-based therapies²⁰.

The concept of using transplantation to replace damaged dopamine neurons with new ones first surfaced in the 1970s. The majority of cell transplantation clinical trials, both domestically in the United States and abroad (such as Sweden, Mexico, etc.), have yielded inconsistent to subpar outcomes²².

Dopamine depletion is thought to be the cause of the desynchronized circadian rhythm that PD patients with sleep difficulties are exhibiting²⁸. It has been shown that bright light treatment, administered with light boxes (up to 10,000 lux) for 30 minutes per session, usually in the morning, is effective in enhancing mood and sleep quality. More investigation is required to determine the most effective strategies and possibilities²³.

Bright light therapy is being utilized to treat sleep disturbances, a non-motor symptom, albeit it is not therapeutic to the extent of disease control as deep brain stimulation, Dopamine depletion is thought to be the cause of the desynchronized circadian rhythm that PD patients with sleep difficulties are exhibiting²¹.

Management of Early PD:

The most popular form of treatment for PD is medication.8 The aim is to address the dopamine deficit, as that is the root cause of the symptoms. Medicinal therapy is typically initiated when symptoms become incapacitating or interfere with day-to-day functioning²². The timing when to start drug treatment in PD, particularly in the very early stages of the illness, when there may be little functional deficit can be difficult. The decision which should be made with full involvement of the patient is determined by the degree of physical impairment balanced against the complications that can be related to drug treatment. Of increasing importance is the issue of whether early treatment confers the potential for neuroprotection²⁴.

At present, therefore, there are no proven neuroprotective therapies with only symptomatic treatments available, If the patient and clinician feel treatment is required, what therapy should be commenced? This decision will be based on the age of the patient, the likelihood of proper compliance, the presence of cognitive impairment, additional medical conditions and the wishes of the patient²⁴. Patients who have little to no handicap may still begin treatment right away. According to one study, untreated PD patients' self-reported health status using the Parkinson's Disease Questionnaire (PDQ)-39 was poorer at initial consultation and for up to 18 months. However, there have been doubts raised about the validity of the rating scale in this patient population²².

The Role of Surgery:

Surgery has been used for Parkinson's disease for more than 50 years. Patients, especially those with severe tremors, were occasionally referred for ablative surgery, usually to the contralateral thalamus, in the early 1950s [24]. After levodopa was introduced, surgical treatment became less popular. It is kind of ironic that surgeons and other healthcare professionals decided to re- examine surgical intervention in light of the increasing awareness of levodopa-related problems²⁶.

Despite receiving the best medical care, the majority of patients will still experience incapacitating symptoms. These patients are candidates for deep brain stimulation, which targets the Globus pallidus interna or the subthalamic nucleus²⁵. When PD symptoms are very severe and medications cannot moderate them, surgery and DBS can be considered as the final options for the treatment. It involves sending electrical impulses to certain parts of the brain (usually SN or globus pallidus, which communicate with the (STN) by a neurostimulator device that is a brain implant known as a ‘brain pacemaker.’ The target area of DBS is usually the subthalamic nucleus (STN)²⁵.

A further development came with the introduction of stimulators. This involved high-frequency deep brain stimulation (DBS) of discrete brain areas producing functional and reversible inhibition of the target site. A number of areas within the basal ganglia can be targeted. The procedure most commonly carried to reduce bradykinesia, tremor and rigidity and which also reduces drug-related motor complications is bilateral subthalamic stimulation²⁴. The stimulation of the dorsolateral STN border alongside the surgery can improve its efficiency (Herzog et al., 2004). Later it was found that stimulation of caudal zona incerta (cZI) can be more effective with fewer complications after the surgery (Plaha et al., 2006)²⁶. Age seems to be less critical in Vim DBS performed for disabling tremor. Recent studies have suggested that DBS of the pedunculopontine nucleus may be beneficial in improving axial stability. Assessment of a patient for DBS requires assessment by an experienced multidisciplinary team²⁴.

CONCLUSION:

Parkinson's disease is one of the most common neurodegenerative diseases affecting the aging population and is associated with an increased morbidity and mortality. Inspired by the numerous remarkable advancements presented here, we hope that services and therapies will keep developing and positively impact Parkinson's disease sufferers all across the world. Numerous theories and investigations have been conducted regarding the causes of the disease, and ultimately it has been determined that there are several elements contributing to its occurrence. Parkinson's disease is mostly caused by a dopamine shortage, which can also be treated with medicine. The main medications that are used to treat this condition are those that lower dopamine levels in the brain. Bradykinesia, rigidity, resting tremor, and postural instability are the main symptoms. These motor symptoms appear when at least 50–60% of nigral dopamine neurons, or 60–80% of their striatal terminals, have disappeared. The future of PD treatment seems bright for patient-specific care that is more successful and has fewer adverse effects, but more investigation is still needed to dig into the under-researched drugs for PD.

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Received on 22.04.2025 Revised on 24.06.2025

Accepted on 26.07.2025 Published on 08.08.2025

Available online from August 14, 2025

Research J. Science and Tech. 2025; 17(3):231-238.

DOI: 10.52711/2349-2988.2025.00032

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