Parkinson’s Disease: A Degenerative Disorder

Parkinson’s Disease: A Degenerative Disorder

Parkinson’s Disease is a neurodegenerative disorder that affects the movement of the limbs.

Known as Parkinson’s disease, it is a common neurological illness that develops as a result of a defect that interferes with the normal functioning of the central nervous system. Parkinson’s disease is caused by the loss of dopamine-producing cells in the substantia nigra, a midbrain area located between the thalamus and the medulla. The exact cause of the demise of these cells has not yet been determined. Problems with mobility such as shaking, stiffness, slowness of movement, and difficulties in walking and gait are the first signs of the disease to manifest themselves. Patients have cognitive impairment as well as behavioural difficulties as the disease develops in their lives. During the most severe stages of the disease, dementia is the most prominent characteristic. Other secondary symptoms include sleep disturbances, emotional difficulties, and sensory difficulties. This illness is most commonly encountered in elderly persons who have reached the age of fifty. When the primary motor symptoms of the disease are taken into consideration, the sickness is referred to as Parkinsonism or Parkinsonian syndrome. This illness is frequently included in the idiopathic group as well, despite the fact that in certain rare instances, genetic origin plays a significant role. A number of studies have convincingly demonstrated that persons exposed to particular pesticides are at increased risk of developing Parkinson’s disease, but the risk reduces in cigarette users. From a pathogenic standpoint, Parkinson’s disease develops as a result of the accumulation of a protein known as alpha-synuclein in the form of inclusions in the brain. These inclusions are referred to as Lewy bodies, which are a kind of inclusion that accumulates in neurons. Dopamine deficiency and dysfunction in specific specialized regions of the midbrain are also thought to be responsible for Parkinson’s disease (PD) development. Aside from the symptoms, brain imaging can be quite useful in confirming the diagnosis of the illness.

Treatment with levodopa and dopamine agonists has been shown to be helpful in the treatment of early symptoms of Parkinson’s disease. As the illness develops, dopamine neurons continue to be lost from the midbrain areas, and a point is reached when medicines are no longer effective in treating the early symptoms of Parkinson’s disease. In the event that this level is reached, another obstacle known as dyskinesia will manifest itself, which will be accompanied with uncontrollable writhing motions. Diet and some forms of therapy, on the other hand, can assist to alleviate some of the symptoms. When medications are no longer helpful, surgery and deep brain stimulation are the only options left, as they can significantly lessen motor symptoms. Studies conducted on animal models have demonstrated that stem cell transplantation, gene therapy, and neuroprotective medicines can all assist to alleviate the debilitating symptoms of Parkinson’s disease. There are other medications available to help with sleep disruptions and emotional difficulties. In honor of the English physician James Parkinson, who published the first thorough description of the condition in An Essay of the Shaking Palsy in 1817, the disease is named after him. The red tulip is the flower that represents this sickness and the globe. Parkinson’s Day is observed on April 11th to commemorate Dr. Parkinson’s life and achievements. A number of well-known individuals, like Michael J. Fox and Muhammad Ali, have been diagnosed with Parkinson’s disease and have worked to raise public awareness of the disease’s effects and treatment options.

Classification

Parkinsonism is the word used to describe a motor condition characterized by tremors at rest, rigidity, slowness of movement, and postural instability as its primary symptoms. Parkinsonian syndrome may be divided into four types, each of which is determined by the cause of the symptoms. Primary or idiopathic Parkinsonism, secondary or acquired Parkinsonism, inherited Parkinsonism, and Parkinson plus syndromes are the subtypes of Parkinsonism. Despite the fact that Parkinson’s disease, also known as primary Parkinsonism, is the most frequent kind of Parkinsonism, the exact origin of this disease remains a mystery. In recent years, research has indicated that genes have a significant influence in the development of this illness. Although Parkinson’s disease (PD) is categorized as a movement illness, it is also responsible for a wide range of non-motor symptoms such as sensory difficulties, cognitive deficits, and sleep disturbances. Multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies are some of the signs of primary Parkinsonism, which is a neurodegenerative disorder. Parkinsonism is classified as a synucleinopathy from a pathophysiological standpoint because of the abnormal accumulation of alpha-synuclein protein in the brain in the form of Lewy bodies. It is possible to compare this illness to Alzheimer’s disease due to the accumulation of tau protein in the form of unexplained neurofibrillary tangles that develops. According to recent findings, there is a clinical and pathological overlap between the tauopathies and the synucleinopathies. Patients with Parkinson’s disease (PD) have had their neurofibrillary tangles removed from their brains. Dementia with Lewy bodies (DLB) is a condition that has certain characteristics with Parkinson’s disease (PD). Although the systematic connection between PD and DLB has been established, the exact nature of this association remains unclear. They can be examined as a group or as separate categories, depending on your preferences.

Symptoms

Parkinson’s disease (PD) causes movement-related issues that result in motor impairments. Other symptoms of severe Parkinson’s disease include non-motor symptoms such as autonomic dysfunction, neuropsychiatric symptoms followed by sensory and sleep issues, and other non-motor symptoms such as nausea and vomiting. The following four motor difficulties are considered to be severe in this disorder: tremors, stiffness, slowness of movement, and postural instability. Tremor is the most often observed sign of Parkinson’s disease. The presence of tremors is not the first sign of the illness in around 30% of patients; instead, they appear later as the disease advances. The rest tremor is the most common of the tremors, and its frequency increases while the limb is at rest, but it diminishes when any purposeful activity is performed or when the patient is asleep, among other things. It is well known that the distal portion of the leg is the first to be affected by the rest tremor. Initially, just a single hand or leg is affected, but as the disease advances, the tremor grows more widespread and eventually becomes bilateral. The tremor has a frequency of 4-6 hertz and is caused by a muscle contraction. A circular movement known as pill rolling is performed when your index finger comes into touch with your thumb. This is the strategic characteristic of rest tremor and it occurs when your index finger comes into contact with your thumb.

Bradykinesia, or the inability to move quickly, is another important characteristic of Parkinson’s disease. In accordance with its moniker, this ailment is associated with difficulty in doing physical activities. Movements that are sequential and simultaneous become unpleasant. During the later stages of the disease, this symptom becomes more severe and pervasive. Bradykinesia is characterized by difficulty in completing daily tasks such as writing, dressing, and other activities that need fine motor control, such as shaving. The second distinguishing sign of Parkinson’s disease is stiffness, which may be distinguished by the inability of a limb to move in any direction. Rigidity is induced by increased muscular tone, which is generated by the repetitive and disproportionate contraction of muscles. Parkinsonism is characterized by rigidity that can be homogeneous or ratchety. When tremors and increased muscular tone are present, the phrase cogwheel stiffness might be used to describe the situation. Rigidity, which is the first sign of Parkinson’s disease, can be linked with joint discomfort. Rigidity may appear excessive because it has a tendency to cause discomfort in the muscles of the neck and shoulders initially. As the illness develops, stiffness begins to impair all of the body’s motions. Postural instability develops in the latter stages of the condition, resulting in poor balance and the bones being at danger of being broken without warning or provocation. This symptom is typically absent in young individuals, but it becomes more noticeable as the disease progresses in later stages. Patients have frequent falls in around 40% of cases, and approximately 10% of patients experience weekly falls, indicating the severity of the illness. In addition to gait and postural impairments such as festination, speech and swallowing issues such as voice disorders are also present.

Neuropsychiatric issues are a common complication of Parkinson’s disease, and they can range from mild to severe in severity depending on the individual. Cognitive, emotional, behavioral, and thought-process difficulties are all examples of this type of difficulty. As the disease progresses, cognitive impairments may manifest themselves in the early stages and become more severe as the disease progresses. The most common type of cognitive disturbance is executive dysfunction, which is characterized by difficulties with abstract thinking, cognitive flexibility, incorrect behaviors, and the selection of important sensory information. Other issues include sluggish cognitive processing speed and attentional swings. Visuospatial difficulties are also not uncommon in children. The risk of developing dementia in people with Parkinson’s disease (PD) is two to six times higher than the risk in the general population (normal population). In patients suffering from Parkinson’s disease and dementia, resilient support as well as family care is required, as is the case for anybody suffering from a chronic illness.

Patients with Parkinson’s disease and dementia are more likely than the general population to have changes in mood and behavior. Even in individuals who do not have cognitive impairment, these changes can be found in their brains. Depression, anxiety, and apathy are the most frequent types of mood changes experienced by people. Overuse and desire of medications, as well as hypersexuality, are all frequent and are associated with the medications that are employed in the therapy of the condition.. Patients with delusions and hallucinations have been reported in around 4% of cases. This symptom is the result of an overabundance of dopamine in the brain. Other bodily processes can be affected by Parkinson’s disease. Sleep difficulties are quite common in people with Parkinson’s disease and can be exacerbated by medicines. Drowsiness and insomnia are two types of sleep disorders. Changes in the autonomic nerve system can result in oily skin, orthostatic hypotension, excessive perspiration, impaired sexual function, and uncontrolled urine, among other symptoms. In addition, gastric difficulties and constipation grow severe, posing a threat to the patient’s well-being. It is also possible that problems with the eyes and eyesight will manifest themselves, which include reduced blink rate, dry eyes, saccadic movements, decreased ocular pursuit, and impaired vision. It is also observed that the sense of smell has been impaired, as well as the sensation of pain followed by paresthesia. These signs and symptoms manifest themselves long before the disease is officially diagnosed.

 

The vast majority of Parkinson’s disease patients may be classified as having an idiopathic illness, which means that the precise origin of the ailment is unclear. Genetic factors can be attributed to a very small number of instances, which is a very small percentage of all cases. Other variables can be classified as “risky components” that have the potential to develop Parkinson’s disease, but the precise link between them and the illness is still unclear. Although Parkinson’s disease is often believed to be a non-genetic ailment, in around 5% of instances, a mutation in one or more identifiable genes can result in this condition. PD is caused by mutations in the genes SNCA, UCH-L1, PRKN, LRRK2, PINK1, DJ-1, and ATP13A2, which code for alpha-synuclein, ubiquitin carboxy-terminal hydrolase L1, parkin, leucin-rich repeat kinase 2, PTEN-induced putative kinase 1, and ubiquitin carboxy-terminal hydrolase L1. PD is caused by mutation When compared to other genes, a mutation in the LRRK2 gene increases the likelihood of developing Parkinson’s disease. SNCA and LRRK2 are the genes that have been examined the most extensively in relation to Parkinson’s disease. Mutations in the genes SNCA, LRRK2, and glucocerebrocidase (GBA) enhance the chance of developing sporadic Parkinson’s disease. Gaucher’s disease is caused by mutations in the GBA gene.

The role of SNCA in Parkinson’s disease is critical since this gene is responsible for the production of a protein known as alpha-synuclein, which is the primary component of Lewy bodies. The presence of missense mutations in the gene followed by duplication and triplication of the locus has been seen in families with familial Parkinson’s disease. Despite the fact that missense mutations are infrequent, amplification of the SNCA locus is responsible for 2 percent of instances of familial Parkinson’s disease. Asymptomatic carriers have been found to have increased numbers of offspring. The LRRK2 gene is responsible for the production of a protein known as dardarin. Mutations in the LRRK2 gene are the most common cause of sporadic and familial Parkinson’s disease. It accounts for 10% of all familial cases of Parkinson’s disease and 3% of all sporadic occurrences of the disease. According to educated guesses, around 40 distinct gene mutations have been identified as being responsible for Parkinson’s disease.

 

Pathology

 

Parkinson’s disease is characterized by significant damage to the basal ganglia, a collection of brain regions that are innervated by the dopaminergic system and have been labeled as such. In the areas of the substantia nigra and pars compacta, the cells die at an alarmingly high rate. Neuronal loss causes macroscopic changes in the sliced surfaces of the brainstem, which may be seen under a microscope. The pigmentation of melanin in the substantia nigra and the locus coeruleus is similarly reduced throughout this period. The substantia nigra and other areas of the brain exhibit significant neuronal loss as well as a significant buildup of Lewy bodies on histopathology. The death of astrocytes and the activation of microglia are the next steps after neuronal loss. The presence of Lewy bodies in various areas of the brain is the distinguishing characteristic of this condition. The major symptoms of this illness are caused by a decrease in the activity of dopamine-producing neurons, particularly in the substantia nigra and pars compacta areas of the brain.

 

The basal ganglia are linked to various regions of the brain by five main routes. These are as follows: Motor, oculomotor, associative, limbic, and orbitofrontal circuits are among the routes involved. All of these circuits are disrupted in Parkinson’s disease, and as a result, the patient experiences difficulties with movement, attention, and learning. The motor circuit has received the most attention out of the five circuits investigated so far. Since 1980, a conceptual model has been in use that demonstrates a direct link between changes in the motor circuit and the emergence of symptoms of Parkinson’s disease. The model, on the other hand, has been changed in light of current developments in research, but it is still in use today. It is proposed that the basal ganglia have an inhibitory impact on a wide range of motor systems, preventing them from becoming active during inconvenient periods. In the case of a specific motor activity that must be completed, this inhibitory impact is diminished. The release of dopamine has a diminishing influence on this inhibitory effect. High amounts of dopamine are necessary in order to conduct motor activities, but when the level of dopamine drops, symptoms of Parkinson’s disease (PD) have a better chance of manifesting themselves. Hypokinesia is a disorder in which the amount of dopamine in the body decreases, making it harder to perform motor activities properly. The medicines used to treat Parkinson’s disease (PD) may cause excessively high quantities of dopamine to be produced, leading in the activation of motor systems at inopportune periods, resulting in dyskinesias.

 

There are a variety of processes that can lead to the death of brain cells that have been identified. One such mechanism is the aberrant buildup of a protein known as alpha-synuclein, which is involved in Parkinson’s disease. When this protein binds to ubiquitin, it causes neuronal degeneration and death. This protein builds up inside the cells, forming inclusions known as Lewy bodies, which are thought to be responsible for the disease. According to Braak staging, Lewy bodies first develop in the olfactory bulb, medulla oblongata, and pontine tegmentum, before spreading throughout the brain. As the disease develops, Lewy bodies begin to accumulate in the substantia nigra, various regions of the midbrain and basal forebrain, and eventually in the neocortex. It is in these locations that the greatest amount of neuronal death takes place. It is possible that Lewy bodies are not responsible for cell death and may even be protective. In people suffering from dementia, a significant buildup of Lewy bodies has been observed in the cortical regions of their brains. Patients with Alzheimer’s disease who also have dementia may be found to have neurofibrillary tangles and senile plaques in their brains. Some other processes linked with cell death include proteosomal and lysosomal malfunction, which is followed by a decrease in mitochondrial activity. Iron buildup has been seen in the substantia nigra and its surrounding areas.

 

Diagnosis

 

In addition to a medical history and neurological examination, Parkinson’s disease can be diagnosed. At this time, there are no definitive laboratory tests available that can clearly demonstrate that a person is suffering from Parkinson’s disease. Brain scans can aid in the diagnosis of the condition, but the odds of correctness are very low. In some cases, patients may be prescribed levodopa, which can help to alleviate their symptoms of motor impairment while also improving the precision with which the condition is diagnosed. The isolation of Lewy bodies from the midbrain during an autopsy can also indicate that a person has Parkinson’s disease. Parkinsonian syndrome can be caused by a variety of conditions including Alzheimer’s disease, numerous brain infarctions, and drug-induced Parkinsonism. There are a number of criteria that have been established by medical organizations that can be used to identify the disease in its early stages. The Parkinson’s Disease Society Brain Bank in the United Kingdom and the National Institute of Neurological Disorders and Stroke in the United States jointly created the most commonly utilized criteria. The Parkinson’s Disease Society Brain Bank is primarily concerned with rest tremors, slowness of movement, and postural instability.

 

CT and Magnetic Resonance Imaging (MRI) of the brain in people with Parkinson’s disease appear to be normal on initial examination. Secondary signs of Parkinson’s disease, such as basal ganglia tumors, vascular pathology, and hydrocephalus, can be detected with the use of these imaging methods. It is true that diffusion MRI is beneficial in distinguishing between typical and atypical Parkinsonism, although further study is needed in this area. When it comes to monitoring the activity of dopaminergic neurons in the basal ganglia, radiotracers such as PET and SPECT can be employed. The presence of decreased dopaminergic activity in the neurons of the basal ganglia may indicate the presence of this disease.

 

Management

 

Although there is no known cure for Parkinson’s disease at this time, medicine, surgery, and multidisciplinary care can assist people to survive the condition. The most promising medicines for treating motor symptoms are levodopa, dopamine agonists, and MAO-B inhibitors, among other things. These medications are often administered based on the stage of the disease that they are linked with. In general, there are two stages of medicine that may be distinguished. Patient with Parkinson’s disease (PD) experiences some degree of impairment for which he or she requires pharmaceutical therapy in the first phase, and in the second phase, the patient experiences motor symptoms associated with levodopa use. The treatment goal in the initial stage is to reduce the number of adverse effects that have arisen as a result of the increased dopaminergic activity in the brain. The use of other medications, such as dopamine agonists and MAO-B inhibitors, might cause the initiation of levodopa treatment to be delayed. Dyskinesias can be prevented or delayed with the use of these medications. The second phase of medicine is intended to reduce the variations in blood sugar levels that have occurred as a result of the therapy. When medicines fail to produce the intended effects, surgical procedures and deep brain stimulation treatments are used to treat the patient. Palliative care is offered to patients who are nearing the end of their illness in order to improve their quality of life.

 

Levodopa

 

For more than 30 years, levodopa has been used to treat Parkinson’s disease patients in the United States. In the presence of the enzyme dopa decarboxylase, L-DOPA is transformed into dopamine in the dopaminergic neurons of the brain. Because motor symptoms in Parkinson’s disease are caused by a shortage of dopamine in the cells of the substantia nigra, the injection of L-DOPA can temporarily alleviate the symptoms of Parkinson’s disease. According to studies, just 5-10 percent of the L-DOPA reaches the brain’s blood-brain barrier. Despite the fact that L-DOPA is transformed into dopamine, it also has a variety of undesirable side effects such as nausea, dyskinesias, and joint stiffness. Carbidopa and benserazide are both strong peripheral dopa decarboxylase inhibitors that have been studied extensively. They prevent L-DOPA from being converted into dopamine, therefore reducing adverse effects by improving bioavailability of the drug. Levodopa is also associated with dopamine dysregulation syndrome, which is a condition that occurs as a result of excessive usage of the drug. When levodopa dosages are administered intravenously as well as through intestinal infusions, the rate of drug dissemination increases.

 

Tolcapone is known to decrease the activity of the COMT enzyme, which is responsible for the breakdown of dopamine, and as a result, it has been shown to extend the action of levodopa. When levodopa is used in the later stages of the illness, it can cause involuntary movements, known as dyskinesias, as well as fluctuations in reaction to the drug. PD patients who have experienced good response to treatment and few symptoms will experience no response to medication and severe motor symptoms as a result of this occurrence. As a result, it is recommended that levodopa dosages be kept as low as possible in order to maintain the functional stability of the patient. Alternatives to levodopa are already being used in clinical settings.

 

Agonists of dopamine

There are a variety of dopamine agonists that have effects that are comparable to those of levodopa and are known to bind to the dopaminergic post-synaptic receptors in the brain. They are typically used for those who suffer from dyskinesias, and some of the most commonly prescribed medications include bromocriptine, pergolide, piribedil, apomorphine, and lisuride. Although they are known to have substantial effects, they are also known to have some moderate side effects, which include sleepiness, hallucinations, sleeplessness, nausea, and constipation, among other things. It is possible that adverse effects will manifest themselves at extremely low dosages, requiring the physician to seek an alternative medication. These medications are effective in alleviating the motor symptoms produced by misuse of medications, as well as in treating the symptoms that appear during the early stages of the disease. Compared to levodopa, they are more costly, and while dyskinesias caused by dopamine agonists are infrequent in younger individuals, other symptoms may appear as the patient’s age and the illness progresses.

A class of drugs known as MAO-B inhibitors

These medications have been shown to raise dopamine levels in the basal ganglia by interfering with the metabolism of dopamine. They have been shown to suppress the activity of monoamine oxidase-B, which is responsible for the breakdown of dopamine released by dopaminergic neurons. The striatum’s L-DOPA levels rise as a result of a decrease in the activity of the MAO-B enzyme. However, they are less efficient than levodopa at alleviating the motor symptoms of Parkinson’s disease in its early stages of onset. They have a greater number of adverse effects.

Deep brain stimulation and surgery are two options.

Researches had previously assumed that surgery and deep brain stimulation might be used to cure the motor symptoms of Parkinson’s disease; however, with the discovery of levodopa, the number of surgeries has plummeted dramatically. Surgery is typically reserved for situations in which medications have failed to provide a substantial impact. Surgery in the case of Parkinson’s disease can be divided into two categories: lesional surgery and deep brain stimulation (DBS). The thalamus and subthalamic nucleus are the regions that are targeted for lesions and DBS. DBS is the most widely used surgical therapy, and it includes the insertion of a brain pacemaker, which transmits electrical impulses to particular regions of the brain in response to the patient’s symptoms. Individuals who suffer from motor fluctuations and uncontrollable tremors, as well as those who suffer from severe neuropsychiatric disorders, are more likely to benefit from DBS treatment.

Rehabilitation and dietary modifications

The treatment of speech disorders can be achieved through rehabilitation, however more study is necessary in this field. Although regular physical activity, whether performed in conjunction with or without physiotherapy, can be beneficial in the treatment of problems associated with mobility, flexibility, gait, and other issues, the exercise program must be carried out under the strict supervision of a physiotherapist. Constipation and gastroparesis are common symptoms of Parkinson’s disease, which are caused by damage to the muscles and nerves that govern the digestive process. Doctors advise patients to have a well-balanced diet because swallowing problems may develop as the condition progresses. The procedure of gastrotomy, in which food is given directly to the stomach, is used in some circumstances. Because both proteins and levodopa employ the same transportation pathway in the gut and the blood brain barrier, there is significant rivalry between the two. When both medications are taken at the same time, the efficacy of the medication is reduced. Consequently, when levodopa is used, high-protein meals are discouraged, and the patient is advised to follow a well-balanced Mediterranean diet instead.

Palliative care and future avenues for research

Generally, palliative care is necessary in the last stages of an illness when all available pharmaceutical options have failed to provide relief. The primary goal of palliative care is to improve the patient’s quality of life as much as possible. Strong family support is really beneficial in this situation. After Alzheimer’s disease, Parkinson’s disease is the second most deadly neurological condition. We may conclude by stating that Parkinson’s disease (PD) must be handled seriously since it has the ability to make a person’s life worse if left untreated.

 

 

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