Parkinson’s disease is a common disorder that arises due to some imperfection that amends the normal functioning of the central nervous system. Parkinson’s disease is the outcome of the death of the dopamine-containing cells of the midbrain region identified as substantia nigra. The reason for the death of these cells is still unidentified. The prompt symptoms of the disease are problems related with movement like shaking, rigidity, slowness of movement and difficulty in walking and gait. As the disease progresses the patient suffers from cognitive impairment as well as behavioural problems. Dementia is the most protuberant feature in advanced phases of the disease. Other secondary symptoms are sleep, emotional and sensory problems. This disease is generally found in the old people who have crossed their fifties. When the main motor symptoms are taken into contemplation then the disease is termed as Parkinsonism or Parkinsonian syndrome. This disorder is sometimes also kept under the idiopathic category although some in unusual cases genetic origin also plays a key role. Studies have clearly indicated that the jeopardy of PD escalates if individuals are exposed to certain pesticides although the risk diminishes in tobacco smokers. From the pathological point of view PD crops up due to the accretion of a protein known as alpha-synuclein in the form of inclusions. These inclusions are designated by the term Lewy bodies that accrues in neurons. Inadequate formation and function of dopamine in certain specialized areas of the midbrain are also considered to be accountable for PD. Apart from the symptoms neuroimaging of brain is very helpful in validation of the disease.
Levodopa and dopamine agonists have been found to be effective in treating early symptoms of the disease. As the disease progresses the dopamine neurons endure to get lost from the midbrain regions and a stage arrives when the drugs become futile for treating the early symptoms. When this stage is reached another impediment known as dyskinesia arises that is associated with involuntary writhing movements. Diet and some types of rehabilitation can however help to reduce some symptoms. When drugs become ineffective then surgery and deep brain stimulation is the ultimate solution as it can reduce motor symptoms. Studies carried out on animal models have shown that stem cell transplants, gene therapy and neuro-protective agents can help to reduce the disastrous symptoms of PD. Medications for the sleep disturbances and emotional problems are also accessible. The disease is named after the English doctor James Parkinson who first gave the detailed account of the disease in An Essay of the Shaking Palsy in 1817. Red tulip is the icon of this disease and world Parkinson’s day is celebrated in the memory of Dr. Parkinson on 11th, April. Michael J. Fox and Muhammad Ali are the renowned personalities who also suffered from this disease and helped to engender awareness about the consequences and treatment of PD.
The term Parkinsonism is applied for a motor syndrome whose core symptoms are tremors at rest, stiffness, slowing of movement and postural instability. Parkinsonian syndrome can be classified in four categories depending upon the origin of symptoms. These subtypes are primary or idiopathic, secondary or acquired, hereditary Parkinsonism and Parkinson plus syndromes. Parkinson’s disease is the most common type of Parkinsonism also known as primary Parkinsonism but the applicable cause of this disease is still mysterious. In the topical years studies have directed that genes play a foremost role in this disorder. PD is generally classified as a movement disorder but it is also accountable for many non-motors problems like sensory problems, cognitive impairments and sleep disruptions. The symptoms of the primary Parkinsonism comprise multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and dementia with Lewy bodies. From the pathophysiological point of view Parkinsonism is considered a synucleinopathy as there is anomalous amassing of alpha-synuclein protein in the form of Lewy bodies in brain. This condition can be equated with the Alzheimer’s disease as there is accretion of tau protein the form of inexplicable neurofibrillary tangles. Studies have indicated that there is a clinical and pathological intersection between the tauopathies and synucleinopathies. The neurofibrillary tangles have been segregated from the brains of patients of PD. Dementia with Lewy bodies (DLB) has resemblances with PD. The meticulous association between PD and DLB is still not clear. They may be studied together or can be treated as discrete categories.
PD causes movement allied difficulties resulting in motor problems. Apart from motor problems non-motor problems like autonomic dysfunction, neuropsychiatric problems followed by sensory and sleep difficulties also show their presence in advanced phases of the disease. Four motor problems are contemplated as serious in this disorder and these are tremors, rigidity, slowness of movement and postural instability. Tremor is the very frequently noticed symptom of PD. In about 30% cases tremors do not arise as the first symptom of the disorder but develop later as the disease progresses. Among the tremors the frequency of the rest tremor is high and it escalates when the limb is at rest but fades when any voluntary action is executed or the patient is sleeping. The rest tremor is known to distress the distal part of the limb first. In the beginning only the single hand or leg is encompassed but as the disease progresses this tremor becomes bilateral. The frequency of the tremor ranges between 4-6 hertz. The index finger of the hand comes in contact with the thumb and performs a circular movement known as pill rolling which is the strategic feature of rest tremor.
Slowness of movement also known as Bradykinesia is another crucial feature of PD. As the name signposts this symptom is acquainted with difficulties in performing movements. Sequential and simultaneous movements become intolerable. This symptom becomes more penetrating in later phases of the disease. The prompt symptoms of Bradykinesia are difficulties in performing daily activities like writing, dressing etc. as fine motor control is required. The next distinctive symptom of PD is rigidity which can be recognized by failure of the limb to carry out movement. Rigidity is caused by increased muscle tone due to disproportionate and incessant contraction of muscles. Rigidity may be uniform or ratchety in Parkinsonism. The term cogwheel rigidity can be applied when tremors and increased muscle tone come into play. Rigidity can be associated with joint pain as it is the earlier symptom of PD. Rigidity may be disproportionate as it tends to upset the muscles of neck and shoulders first. As the disease progresses rigidity affects all the movements of body. Postural instability arises in later phase of the disease causing impaired balance and the bones are at the risk of getting fractured effortlessly. This symptom is generally inattentive in the young patients as it ascends in later phase of the disease. About 40% patients fall very frequently and about 10% patients experience weekly fall showing the severity of the disease. Other motor problems embrace gait and posture disturbances like festination, speech and swallowing disturbances like voice disorders.
Neuropsychiatric problems are also an imperative part of Parkinson’s disease and they may range from slight to severe ones. These problems comprise disturbances in cognition, mood, behavior and thought processes. Cognitive problems may arise in the preliminary stages of the disease and can upsurge as the disease advances. The most frequent cognitive disturbance is the executive dysfunction which can be characterized by problems related to abstract thinking, cognitive flexibility, inappropriate actions and selecting relevant sensory information. Slow cognitive speed and fluctuations in attention are other problems. Visuospatial problems are also not uncommon. A person suffering from PD has at two to six times greater risk of getting affected with dementia in comparison to the normal population. Dementia can be coupled with reduced quality of life and resilient support as well as care of the family is necessitated for the patents suffering from PD and dementia.
Mood and behavior alterations are very frequent in patients of PD with dementia. These alterations are also present in patients without cognitive impairment. Depression, anxiety and apathy are the most common mood alterations. Medication overuse and craving, hypersexuality is also common and is related with the medication which is used in the management of the disease. Delusions and hallucinations have been notified in about 4% patients. This symptom is the upshot of the dopaminergic excess. PD can also disturb other functions of body. Sleep problems are very frequent if PD and can be deteriorated by medications. Sleep disturbances comprise drowsiness and insomnia. Alterations in the autonomic nervous system cause oily skin, orthostatic hypotension, excessive sweating, altered sexual function and uncontrolled urination. Gastric problems and constipation also become severe and can jeopardize patient’s health. Problems related to eye and vision also come into action and comprise of declined blink rate, dry eyes, saccadic movements, decreased ocular pursuit and blurred vision. Impaired sense of smell and sensation of pain followed by paresthesia are also noticed. These symptoms make their appearance much before the diagnosis of the disease.
Most patients of Parkinson’s disease can be placed in the category of idiopathic disease as the meticulous cause of the disorder is unknown. A very trivial portion of cases can be cogitated under the category of genetic factors. Other factors can be placed under the category of risky elements that may cause PD but the precise relationship between them and the disease is still vague. PD is generally considered a non-genetic disorder but in about 5% cases mutation in some unambiguous genes can result in this disorder. The genes namely SNCA, UCH-L1, PRKN, LRRK2, PINK1, DJ-1 and ATP13A2 code for alpha-synuclein, ubiquitin carboxy-terminal hydrolase L1, parkin, leucin-rich repeat kinase 2, PTEN-induced putative kinase 1 and mutations in any of these gene can result in PD. Mutation in LRRK2 gene proliferates the chances of occurrence of PD in comparison with other genes. SNCA and LRRK2 are the most comprehensively studied PD-related genes. Mutations in SNCA, LRRK2 and glucocerebrocidase (GBA) increase the risk of sporadic PD. Mutations in GBA result in Gaucher’s disease.
Role of SNCA is very vital in PD as this gene is accountable for the formation of a protein known as alpha-synuclein which is the foremost element of Lewy bodies. Missense mutations of the gene followed by duplication and triplication of the locus have been noticed in groups with familial PD. Although missense mutations are intermittent but multiplication of the SNCA locus account for 2% of cases with familial PD. Multiplications have been noticed in the asymptomatic carriers. LRRK2 gene codes for a protein known as dardarin. Mutations in the LRRK2 gene are primarily accountable for sporadic and familial PD. It accounts for 10% of familial and 3% of the sporadic cases of PD. According to a guesstimate about 40 different mutations in genes have been found to be blamable for PD.
A group of brain structures which are innervated by dopaminergic system and identified as basal ganglia are severely damaged in Parkinson’s disease. The cells in the regions of substantia nigra and pars compact die very frequently. Macroscopic alterations can be identified in the cut surfaces of the brainstem due to neuronal loss. The melanin pigmentation also reduces in the substantia nigra and locus coeruleus. Histopathology of substantia nigra and other regions of brain show heavy neuronal loss as well as heavy accumulation of Lewy bodies. Neuronal loss is followed by death of astrocytes and activation of the microglia. Presence of Lewy bodies in different regions of brain is the key feature of this disorder. The primary symptoms of this disease are due to the reduced activity of dopamine producing neurons especially in the regions substantia nigra and pars compacta.
Basal ganglia are connected to other areas of brain through five major pathways. These pathways are motor, oculo-motor, associative, limbic and orbitofrontal circuits. In PD all these circuits are disturbed and so the patient suffers from the problems associated with movement, attention and learning. Out of all the five circuits, motor circuit has been intensively studied. A conceptual model has been in practice since 1980 which shows direct relationship between alteration of motor circuit and appearance symptoms of PD. The model is however, modified with recent advances in research but is still used even today. According to this model, the basal ganglia exert an inhibitory influence on a wide range of motor systems that prevents them from being active at inappropriate times. When a particular motor action has to be performed then this inhibitory effect is reduced. This inhibitory effect diminishes with the release of dopamine. High levels of dopamine are required in order to perform motor actions but if the level of dopamine declines symptoms of PD get a chance to make their appearance. The condition in which the level of dopamine declines is known as hypokinesia and causes difficulty in motor actions. The drugs that are used to treat PD may produce excessive high levels of dopamine resulting in activation of motor systems at inappropriate times causing dyskinesias.
A number of mechanisms are known in which loss of brain cells is observed. One such mechanism consists of abnormal accumulation of a protein known as alpha-synuclein. This protein combines with ubiquitin and results in neuronal loss. This protein accumulates inside the cells in the form of inclusions known as Lewy bodies. According to Braak staging Lewy bodies first make their appearance in the olfactory bulb, medulla oblongata and pontine tegmentum. As the disease progresses Lewy bodies start accumulating in substantia nigra, areas of midbrain and basal forebrain and later in the neocortex. These areas are the chief sites where heavy neuronal loss occurs. Lewy bodies may not be responsible for cell death and may be protective. In the patients suffering from dementia heavy accumulation of Lewy bodies have been noticed in the cortical areas. Neurofibrillary tangles and senile plaques may be observed in patients of Alzheimer’s disease with dementia. Other mechanisms associated with cell death are proteosomal and lysosomal dysfunction followed by reduced mitochondrial activity. Iron accumulation has been noticed in the regions of substantia nigra.
Parkinson’s disease can be diagnosed by medical history and neurological examination. There are at present no definite laboratory tests available that can clearly depict that a person is suffering from PD although brain scans help in disease identification but the chances of accuracy are low. The patients may be given levodopa which results in reduction of problems of motor impairment and the disease can be diagnosed with greater accuracy. Isolation of Lewy bodies from the midbrain by autopsy also confirms that a person is suffering from PD. Alzheimer’s disease, multiple cerebral infarctions and drug-induced Parkinsonism can also produce Parkinsonian syndrome. Medical organizations have created certain criteria by which the disease can be diagnosed in early phases. The most widely used criteria have been developed by the UK Parkinson’s Disease Society Brain Bank and US National Institute of Neurological Disorders and Stroke. The PD Society Brain Bank focuses on rest tremors, slowness of movements and postural instability.
Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) of brain of the patients of PD appear to be normal. These techniques can be useful in identification of the secondary symptoms of PD like basal ganglia tumors, vascular pathology and hydrocephalus. Diffusion MRI is however, useful in differentiation of typical and atypical Parkinsonism but more research is required in this field. PET and SPECT radiotracers can be used for measuring the activity of dopaminergic neurons in the basal ganglia. Reduced dopaminergic activity in the neurons of basal ganglia can be a clue for this disorder.
In the present scenario there is no possible cure for Parkinson’s disease but medication, surgery and multidisciplinary management can help the patients to survive. The most promising drugs used to curing the motor symptoms are levodopa, dopamine agonists and MAO-B inhibitors. These drugs are generally prescribed on the basis of the phase of the disease associated. In general terms two stages of medications are identified. In the initial phase the patient with PD develops some disability for which he or she requires pharmacological treatment and in the second phase the patient develops motor symptoms related to levodopa usage. The treatment in the initial stage aims at minimizing the side effects that have resulted from the enhanced dopaminergic activity. The starting of the levodopa treatment can be delayed by the usage of other drugs like dopamine agonists and MAO-B inhibitors. These drugs can delay the onset of dyskinesias. The second phase of medication aims at reducing the fluctuations that have resulted as a result of treatment. When medications fail to give the desired results then surgery and deep brain stimulation methods are employed. In the final stages of disease palliative care is provided in order to enhance the quality of life.
Levodopa has been used for the treatment of Parkinson’s disease for more than 30 years. In the dopaminergic neurons L-DOPA is converted into dopamine in the presence of dopa decarboxylase. As motor symptoms in PD are caused by the lack of dopamine in the cells of substantia nigra, the administration of L-DOPA can help to diminish the motor symptoms temporarily. Studies have indicated that only 5-10% of the L-DOPA crosses the blood brain barrier. Although L-DOPA is converted into dopamine but it produces a number of side effects also like nausea, dyskinesias and joint stiffness. Carbidopa and benserazide are potent peripheral dopa decarboxylase inhibitors. They block the conversion of L-DOPA to dopamine therefore reduce side effects by increasing bioavailability. Levodopa is also related to dopamine dysregulation syndrome which is the result of overuse of the medication. If the doses of levodopa are given intravenously and through intestinal infusions, then the rate of spread of medication increases.
Tolcapone is known to inhibit the COMT enzyme activity which is responsible for the degradation of dopamine and this in turn prolongs levodopa activity. Usage of levodopa in later phases of the disease results in involuntary movements also known as dyskinesias and fluctuations in response to medication. When this happens the patient of PD switches from good response to medication and few symptoms to no response to medication and significant motor symptoms. Therefore, it is advised to keep the doses of levodopa low in order to maintain the functional stability of the patient. Use of alternatives for levodopa is now in practice.
A number of dopamine agonists are known that have similar effects like that of levodopa and are known to bind the dopaminergic post-synaptic receptors. They are generally used for the individuals suffering from dyskinesias and the common examples are bromocriptine, pergolide, piribedil, apomorphine and lisuride. Although they are known to produce significant effects but also cause some mild side effects namely drowsiness, hallucinations, insomnia, nausea and constipation. Sometimes in very mild doses side effects emerge out so the physician has to search for another drug. These drugs are useful for curing the motor symptoms caused by overuse of medication and are useful for treating the symptoms that arise during the initial phases of the disease. They are more expensive than levodopa and dyskinesias due to dopamine agonists are however, rare in younger people but other symptoms may crop up as the age as well as the disease advances.
These drugs are known to increase dopamine levels in the basal ganglia by blocking it metabolism. They are known to inhibit the activity of monoamine oxidase-B that breaks down dopamine secreted by the dopaminergic neurons. Reduction in the activity of MAO-B increases the levels of L-DOPA in striatum. They are used to improve the motor symptoms in early phases of the disease but are less effective than levodopa. They produce more side effects.
Surgery and deep brain stimulation
Researchers earlier believed that surgery and deep brain stimulation can help to treat the motor symptoms of PD but with the discovery of levodopa the number of operations experienced a heavy downfall. Surgery is generally performed in those cases where drugs fail to produce significant effect. Surgery in case of PD can be placed under two group namely lesional and deep brain stimulation (DBS). The target areas for lesions and DBS are thalamus and subthalamic nucleus. DBS is the most commonly used surgical treatment and it involves use of brain pacemaker that sends electrical impulses to specific areas of brain. DBS is generally used for the individuals who suffer from motor fluctuations and uncontrolled tremors or those who suffer from sever neuropsychiatric problems.
Rehabilitation and diet
Speech problems can be cured with rehabilitation although more research is required in this area. Regular physical exercise with or without physiotherapy can be helpful for treating the problems associated with mobility, flexibility, gait etc. although the exercise program must be practiced under the strict supervision of the physiotherapist. Muscles and nerves that take control over the digestive process are generally affected in PD resulting in constipation and gastroparesis. A balanced diet is recommended by the doctors as swallowing difficulties may occur as the disease advances. In some cases gastrotomy is practiced where food is directly delivered in the stomach. Strong competition occurs between proteins and levodopa as both uses the same transportation system in the intestine and blood brain barrier. When both are taken together the effectiveness of the drug decreases. Therefore, when levodopa is taken heavy protein diets are discarded and the patient is suggested to take balanced Mediterranean diet.