Parkinson’s Disease: Neuroscience of Aging Research Paper

Introduction

Parkinson’s disease is a common progressive neurodegenerative disease, which affects the basal ganglia of the brain. The disease is characterized by a progressive loss of dopaminergic neurons, especially in the substantia nigra pars compacta (SNpc). The clinical feature of Parkinson’s disease is characterized by difficulty with coordinated movement; this includes asymmetric resting tremors, rigidity, and bradykinesia. Psychiatric symptoms are also frequently seen in Parkinson’s disease.

Pharmacological treatment is the mainstay of treatment but there are surgical options.

Etiology

The exact cause of Parkinson’s disease is not known. One suggested cause is exposure to an unknown environmental toxin (Aminoff, 1998). Alternatively, or additionally, endogenous toxins may be responsible (Aminoff, 1998). It is not clear if there is a genetic basis for the disease. Recent work with positron emission tomography (PET) has shown that asymptomatic twins of Parkinsonian patients commonly have abnormalities of striatal dopamine uptake (Aminoff, 1998). The intake of certain drugs (e.g., metoclopramide, haloperidol) and the occurrence of cerebrovascular disease (e.g., multiple lacunar strokes) can lead to secondary parkinsonism (Young, 1999).

Pathogenesis

Although the exact cause of Parkinson’s disease is not known, the pathogenesis involves various inflammatory processes (Teismann & Schulz, 2004).

The affected area of the brain contains activated microglia and reactive astrocytes (to a lesser extent).

This is also associated with cell loss and contributes to the inflammatory process by the release of pro-inflammatory prostaglandins or cytokines (Teismann & Schulz, 2004.)

The dopaminergic neurons of the substantia nigra are especially prone to oxidative and inflammatory damage. The microglia (which functions as the phagocytes of the brain) may be the main contributors to the inflammatory process since a large number of superoxide anions and other neurotoxins are produced by the microglia (McGeer & McGeer, 2007).

Not much is known about the contribution of astrocytes to the inflammatory process (McGeer & McGeer, 2007).

However, the astrocytes can produce both inflammatory and anti-inflammatory molecules, and this may contribute to modulating the activity of the microglia (McGeer & McGeer, 2007).

Current knowledge does not support the role of oligodendrocytes in promoting inflammation (McGeer & McGeer, 2007). However, the oligodendrocytes may also be damaged by the inflammatory process like the neurons (McGeer & McGeer, 2007). In short, the mechanism by which activated microglia specifically targets dopaminergic neurons could be the critical missing link in the pathogenesis of Parkinson’s disease (Rogers et al., 2007.)

Several mechanisms have been proposed to explain the cause of neuronal death in Parkinson’s disease (Jellinger, 2000). Central to this is the programmed versus passive cell death (apoptosis versus necrosis) mechanism (Jellinger, 2000).

However, mechanisms distinct from classical apoptosis might also play a role in the pathogenesis of Parkinson’s disease (Jellinger, 2000). There is some controversy whether the cell death occurs as a result of a single event due to aging or if it is due to an ongoing pathologic process (Banati, Daniel, Blunt, 1998.)

Areas of the brain affected

The symptoms of Parkinson’s disease are caused by the loss of nerve cells in the pigmented substantia nigra pars compacta (SNpc) and the locus coeruleus in the midbrain (Aminoff, 1998).

Cell loss also occurs in the globus pallidus and the putamen. Eosinophilic intraneural inclusion granules (Lewy bodies) are present in the basal ganglia, brainstem, spinal cord, and sympathetic ganglia (Aminoff, 1998).

The substantia nigra pars compacta (SNpc) neurons provide the dopaminergic input to the striatum (part of the basal ganglia) (Aminoff, 1998).

These dopaminergic neurons and the cholinergic striatal interneurons modulate an inhibitory output to the globus pallidus internal and pars reticulata of the substantia nigra (direct pathway) (Aminoff, 1998). Stimulation of the direct pathway in the striatum disinhibits these thalamic nuclei, which in turn increases the excitatory output to the motor region of the cerebral cortex (Aminoff, 1998).

There is an alternative indirect pathway from the striatum, which reduces the excitatory output from these thalamic nuclei to the motor cortex (Aminoff, 1998).

In Parkinson’s disease, the loss of dopaminergic cells in the substantia nigra leads to striatal dopamine depletion (Aminoff, 1998). Since dopamine activates excitatory receptors in the direct pathway and represses inhibitory receptors in the indirect pathway, dopamine depletion leads to decreased activity of the direct pathway and increased activity of the indirect pathway (Aminoff, 1998).

The net result is a reduced thalamic excitation of the motor cortex. Other neurotransmitters like norepinephrine are also depleted, which probably contributes to the depression seen in Parkinson’s disease (Aminoff, 1998).

Clinical manifestations

There is a typical resting tremor (4-6 Hz), which worsens with emotional stress. It often begins with rhythmic flexion-extension of the fingers, hand, or foot, or with rhythmic pronation-supination of the forearm (Aminoff, 1998). The tremor may be confined initially to one limb or the two limbs of one side; later, this may become more generalized (Aminoff, 1998). The tremors may also involve the mouth and chin. In 10-15 % of patients, the tremor is faster (7-8 Hz) and postural, which resembles essential tremor (Aminoff, 1998.)

Rigidity (defined as an increase in the resistance to passive movement) is a common clinical feature in Parkinson’s disease (Aminoff, 1998). This rigidity is the reason for the typical flexed posture of many patients (Aminoff, 1998). Bradykinesia, which is a slowness of voluntary movement and an associated reduction in automatic movements (like swinging of arms while walking), is a disabling feature of Parkinson’s disease. In its more severe form, it leads to akinesia (Aminoff, 1998).

The facial expression is fixed, with widened palpebral fissures and infrequent blinking. There may be blepharoclonus (fluttering of the closed eyelids), blepharospasm (involuntary closure of the eyelids), and drooling of saliva from the mouth (Aminoff, 1998). The voice is hypophonic and poorly modulated. Although the power is preserved, fine or rapidly alternating movements are impaired (Aminoff, 1998). The handwriting is often illegible, small, and tremulous due to a combination of tremor, rigidity, and bradykinesia (Aminoff, 1998).

The patients often have difficulty in rising from the bed or an easy chair and tend to adopt a flexed posture when erect (Aminoff, 1998). It is often difficult for patients with Parkinson’s disease to initiate walking and they may have to increasingly lean forward until they can advance forwards (Aminoff, 1998). They walk with small, shuffling steps, have no arm swing, are unsteady (especially on turning), and may have difficulty in stopping (Aminoff, 1998). Some patients walk with a festinating gait (walking at an increasing speed to prevent themselves from falling due to their abnormal center of gravity) (Aminoff, 1998).

The tendon reflexes are unaltered, and the plantar responses are flexor (Aminoff, 1998). On tapping the glabella repetitively, a sustained blink response is elicited (Myerson’s sign) (Aminoff, 1998).

Psychiatric symptoms in Parkinson’s disease include anxiety, affective and psychotic disorders (hallucinations, delirium), sexual, sleep, and cognitive problems (Castro-García, Sesar-Ignacio & Ares-Pensado, 2004). In advanced cases, an impaired cognitive function can lead to dementia (Aminoff, ). These psychiatric symptoms seen in Parkinson’s disease may either be due to the disease itself or as a consequence of the treatment (Castro-García, Sesar-Ignacio & Ares-Pensado, 2004).

Current treatment

The initial treatment of motor symptoms of Parkinson’s disease includes levodopa, dopamine agonists, anticholinergic agents, amantadine, and selective monoamine oxidase B (MAO-B) inhibitors (Hermanowicz & Haske-Palomina, 2006). The dopamine agonists include ropinirole, pramipexole, pergolide, and bromocriptine.

The two most commonly prescribed dopamine agonists include ropinirole and pramipexole (Hermanowicz & Haske-Palomina, 2006).

The newer dopamine agonists (cabergoline, pramipexole, ropinirole) selectively target D2 receptors and thus may delay the introduction of levodopa and thereby, the occurrence of levodopa-induced dyskinesias. Moreover, they are efficient as adjunctive therapies in advanced Parkinson’s disease (Gottwald et al., 1997.)

Rotigotine is another dopamine agonist, which will be available soon as a daily skin patch (Hermanowicz & Haske-Palomina, 2006). The mainstay of treatment is with levodopa and dopamine agonists (Hermanowicz & Haske-Palomina, 2006).

The anticholinergic medications like trihexyphenidyl and benztropine are the second-line agents of treatment, although they may be associated with side effects like dry mouth, blurred vision, and exacerbation of constipation, and cognitive dysfunction (Hermanowicz & Haske-Palomina, 2006).

Patients with mild symptoms without a requirement for levodopa or a dopamine agonist can benefit from amantadine. It is also the only drug that is effective in reducing dyskinesia. However, amantadine is associated with side effects like hallucinations, peripheral edema, and livedo reticularis (Hermanowicz & Haske-Palomina, 2006).

MAO-B inhibitors are agents that can selectively inhibit monoamine oxidase type B (Hermanowicz & Haske-Palomina, 2006). Selegiline was the first such available drug and has been approved as an adjunct treatment to those having a loss of effectiveness with carbidopa/levodopa alone (Hermanowicz & Haske-Palomina, 2006).

Recently, rasagiline has been approved as monotherapy for mild Parkinson’s disease and as an adjunct to levodopa for those patients with fluctuating symptoms (Hermanowicz & Haske-Palomina, 2006).

Safinamide is another MAO-B inhibitor, which is in phase III development, and may have the added benefit of having combined MAO-B and dopamine reuptake inhibition (Fernandez & Chen, 2007)

Other agents used in the treatment of Parkinson’s disease include catechol-O-methyltransferase (COMT) inhibitors, which inhibit the degradative pathway of levodopa (Hermanowicz & Haske-Palomina, 2006). The COMT inhibitors include entacapone and tolcapone (Gottwald et al., 1997.)

For patients with dystonia or blepharospasm, injections of botulinum toxin can be beneficial (Young, 1999.)

Surgical treatment

Unilateral posteroventral pallidotomy (PVP) or thalamotomy has been utilized for relieving the rigidity, bradykinesia, and tremors in patients with advanced Parkinson’s disease, and in whom antiparkinsonian medication is ineffective or poorly tolerated. PVP is superior to classical thalamotomy (Li Y & Iacono, 1998).

Bilateral posteroventral pallidotomy (BPPV) may significantly improve the bilateral signs of Parkinson’s disease and is safer than bilateral thalamotomy (Li Y et al., 2000).

Fetal nigral transplantation, in which fetal midbrain dopaminergic (nigral) cells are transplanted into the putamen has been tried but it remains an experimental procedure.

It has been observed in experimental models of parkinsonism that fetal nigral grafts could survive, secrete dopamine, form synaptic connections with host neurons, and reverse the behavioral disturbances seen in Parkinson’s disease.

Preliminary clinical trials conducted on fetal nigral transplantation in Parkinson’s disease have shown increased striatal fluorodopa uptake (with positron emission tomography) and clinical benefit in few patients (Olanow et al., 1996).

Transplantation of autologous adrenal medullary tissue has also been attempted with mixed results. In this procedure, the benefit is seen more in patients younger than 50 years of age.

Stellate ganglion transplantation into the striatum of patients with Parkinson’s disease has been recently developed (Komai, 1993). This is safe and more effective than the Transplantation of adrenal medullary tissue (Komai, 1993).

Currently, the most common type of surgical treatment practiced for Parkinson’s disease is deep brain stimulation (DBS) (Hermanowicz & Haske-Palomina, 2006). This surgery may be considered when additional symptomatic control is required or if patients have severe motor complications despite an optimal pharmacological therapy (Chen & Swope, 2007)

In this procedure, an electrode is permanently placed in the subthalamic nucleus of the brain (usually on both sides of the brain) (Hermanowicz & Haske-Palomina, 2006).

An electrical current to this location helps in reducing the symptoms like tremors, stiffness, and slowness of the contralateral limbs (Hermanowicz & Haske-Palomina, 2006). Although this procedure may not eliminate the need for medication in all patients, a few can at least temporarily discontinue their medication (Hermanowicz & Haske-Palomina, 2006). It is also not effective for patients not responding to levodopa.

The ideal candidates for DBS are those who respond well to dopaminergic agents but for a short period (2 hours or less), patients who have dyskinesias that cause functional impairment, and patients who are aged 60 years or younger (Hermanowicz & Haske-Palomina, 2006).

Other treatment modalities

Physical activity, especially aerobic exercise, can help patients with PD to maintain optimal mobility (Hermanowicz & Haske-Palomina, 2006). Walking on a level surface, pedaling a stationary bicycle, exercises like tai chi and qi gong, daily stretching, Pilates, yoga, and pool aerobics may be beneficial (Hermanowicz & Haske-Palomina, 2006).

An ideal exercise program, which includes aerobic exercise, stretching exercises, and strengthening exercises, should last for about twenty minutes at the frequency of three times a week (Chuma, 2007). The use of rhythmic sounds and music therapy might be beneficial to improve gait disorder and motor performance in patients with Parkinson’s disease (Chuma, 2007). Patient education programs are a valuable adjunct to medical therapy, especially in the early and middle disease stages of the disease (Chuma, 2007).

Occupational therapy may also be useful in Parkinson’s disease (Deane et al., 2001.a). An occupational therapist helps in patient support and serves to maintain the patient’s level of self-care, work, and leisure activities for an optimum period. Occupational therapy also helps the patient to change and adapt to their physical and social environment and to develop new activities and roles (Deane et al., 2001.a)

Since progressive disability is a common outcome of Parkinson’s disease, even with optimal medical and surgical therapies, adequate physiotherapy is a must (Deane et al., 2001. b). Physiotherapy improves functional ability and reduces secondary complications (Deane et al., 2001. b). Movement rehabilitation is practiced along with education and support for the affected person. However, it is still not clear which form of physiotherapy is the most effective (Deane et al., 2001. b.)

Referral of patients to physical therapists can be practiced to assess balance, for training to reduce the risk of falls, and for the development of an optimal exercise regimen (Hermanowicz & Haske-Palomina, 2006). Referral of patients to speech pathologists may also be required for patients with dysarthria and dysphagia not responding well to medication (Hermanowicz & Haske-Palomina, 2006). Dysarthria is common in Parkinson’s disease and as much as 20% of patients with Parkinson’s disease might require speech and language therapy (S & LT) (Deane et al., 2001. c). Speech and language therapy aims to improve the speech intelligibility of the patient (Deane et al., 2001. c).

Rehabilitative therapies, participating in community activities, and socializing can be helpful. Support groups can be helpful in a few cases (Hermanowicz & Haske-Palomina, 2006).

Some of the other therapies include nutritional counseling and techniques to help patients manage emotional and cognitive changes occurring in Parkinson’s disease (Young, 1999).

Future research

Promising areas of research in the treatment of Parkinson’s disease include gene therapy, neurotrophic factors, and stem cell therapy. Probably, the ultimate treatment, which is being currently being explored, may lie in identifying those persons at a risk for developing Parkinson’s disease stopping the disease process before it becomes clinically manifest (Hermanowicz &Haske-Palomina, 2006)

Stem-cell transplantation has been researched for treating neurodegenerative disorders like Parkinson’s disease (Hermanowicz &Haske-Palomina, 2006). Stem cells have the potential to supply an unlimited amount of optimal dopaminergic neurons (Snyder & Olanow, 2005). When compared to fetal mesencephalic transplants, stem-cell transplantation can provide better benefits (Snyder & Olanow, 2005).

A new study has reported that mouse embryonic stem (ES) cells have developed into functional dopaminergic neurons after they were transplanted into the host brain damaged by Parkinson’s disease (Hermanowicz &Haske-Palomina, 2006). Although rapid advances have also been made in enhancing and optimizing the yield of dopamine neurons from stem cells, it should be noted that the cell survival and behavioral responses would be limited (Snyder & Olanow, 2005).

Although stem-cell transplantation for Parkinson’s disease is not a new concept, there are numerous ethical and practical issues on the use of aborted fetal tissue. Therefore, it is important to find an alternative source of dopaminergic neurons (Love, 2002).

Glial cell line-derived neurotrophic factor (GDNF) has demonstrated in animal models of Parkinson’s disease of being able to rescue degenerating dopaminergic cells. When GDNF was provided continuously (either with the use of a viral vector or through continuous infusion) into the cerebral ventricles (ICV) or directly into the denervated putamen of animal models, it showed an ability to provide both neuroprotective and neurodegenerative effects.

This success with GDNF prompted a human study in which GDNF was administered as bolus intracerebroventricular injections every month. However, this study showed no clinical benefit, with the occurrence of significant side effects.

In another open-label study of continuous intraputamenal GDNF infusion in five patients, good clinical benefit, tolerance, and fewer side effects were noted. These positive effects were noted within three months after starting the treatment. In addition, the clinical improvement, which was noted, was both sustained and progressive.

Within two years, patients showed an improvement in their off-medication motor and activities of daily living, ranging from 57 to 63% (Patel & Gill, 2007.)

Cerebral transplantation is another potential treatment for Parkinson’s disease. Although good results and feasibility were noted in animal models, studies involving subhuman primates have been limited. Further refinements in the technique and other technical issues have to be taken care of before cerebral transplantation becomes a viable option (Ahlskog, 1993)

Conclusion

Parkinson’s disease is a progressive neurodegenerative disease affecting the basal ganglia of the brain.

There is a progressive loss of dopaminergic neurons, especially in the substantia nigra pars compacta (SNpc). Although the exact cause of Parkinson’s disease is not known, the pathogenesis involves various inflammatory processes. Endogenous and exogenous toxins, as well as genetic factors, may play a role in the etiology of Parkinson’s disease.

The clinical features of Parkinson’s disease include asymmetric resting tremors, rigidity, and bradykinesia.

Psychiatric symptoms are also frequent, and they include anxiety, affective disorders, hallucinations, delirium, sexual, sleep, and cognitive problems. Pharmacological treatment includes levodopa, dopamine agonists, anticholinergic agents, amantadine, and selective monoamine oxidase B (MAO-B) inhibitors.

The surgical treatments that have been tried with varying success include pallidotomy and thalamotomy, transplantation of autologous adrenal medullary tissue, and stellate ganglion transplantation. Currently, the most common type of surgical treatment practiced for Parkinson’s disease is deep brain stimulation. Fetal nigral transplantation is at an experimental stage.

Other treatment modalities include physical exercise, music therapy, physiotherapy, occupational therapy, speech and language therapy, rehabilitative therapies, participating in community activities, socializing, being involved with support groups, and patient education programs. Promising areas of future research in the treatment of Parkinson’s disease include gene therapy, neurotrophic factors, and stem cell therapy, cerebral transplantation.

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