Parkinson’s Disease

Parkinson’s disease (PD) is a degenerative and progressive disorder. It affects nerve cellsThe basic structural and functional units of life. in deepAway from the surface of the body. parts of the brain called the basal nucleiClusters of neurons in the brain that help regulate movement and coordination.. This part was formerly called the basal ganglia. It also affects the substantia nigraA midbrain structure involved in movement and dopamine production., an area of the midbrainThe upper portion of the brainstem involved in visual and auditory processing..

Nerve cells in the substantia nigra produce the neurotransmitterChemicals that transmit signals across synapses. dopamineA catecholamine neurotransmitter involved in motor control, motivation, and reward.. They are responsible for relaying messages that plan and control body movementA fundamental property of life involving motion of the body or its parts..  As the substantia nigra manufactures dopamine, it also produces melaninA brown-black pigment made by melanocytes in the stratum basal and given to keratinocytes as melanos as a waste product. This melanin is the same pigment produced by melanocytesCells in the stratum basale that produce melanin, the pigment responsible for skin color. in the stratum basaleThe deepest layer of the epidermis, where new skin cells are formed. of the epidermisThe outermost layer of the skin, made of stratified squamous epithelium.. It gives the substantia nigra a dark color.  For reasons not yet understood, the dopamine-producing nerve cells of the substantia nigra begin to die off in some individuals.  As the substantia nigra reduces dopamine production, it loses the dark color caused by the accumulation of melanin.  

This chart depicts the five stages of Parkinson’s and the accumulation of motor symptomsSubjective experiences reported by the patient (e.g., nausea, fatigue). resulting from the loss of dopamine.

Stage	Symptoms
1	One side of body affected with mild tremor, some arm rigidity, patient leans to affected side
2	Bilateral changes. Early postural decline – slow shuffle gait, decrease stride length
3	Definite gait disturbance, generalized disability, major problems with balance, tremor, rigidity, bradykinesia
4	Significant disability, limited ambulation with assistance
5	Loss of independent function, mobility.  Severe brady kinesia

Stage 3 of Parkinson’s corresponds to roughly 20% of normal dopamine production. 

The general symptoms of Parkinson’s can be described by this acronym:

T – Tremor

R – Rigidity

A – Akensia

P – Postural inability

The basal nucleiClusters of neurons in the CNS responsible for processing information. and cerebellumThe brain region responsible for balance, coordination, and fine motor control. are responsible for ensuring that movement is carried out in a smooth, fluid manner.  The basal nuclei are gray matterThe inner portion of the spinal cord composed mostly of neuron cell bodies and synapses.. They consist mostly of cell bodies, which is why the term nuclei is more appropriate. They are found deep within the brain.  The three main gray matter bundles of the basal nuclei are the caudate nucleusA structure in the basal nuclei involved in motor processes and learning., the putamenA part of the basal nuclei involved in motor control., and the globus pallidusPart of the basal nuclei that helps regulate voluntary movement.. It has an internal and an external area.  The striatum, also called the corpus striatumA part of the basal nuclei involved in movement and reward processing., is composed of the caudate nucleusThe control center of the cell that contains DNA and directs cellular activities. and the putamen. It is generally involved in receiving intentions of movement. These intentions come from the thalamusThe brain’s relay center, sending sensory information to the cerebral cortex. or from the premotor cortex.  The putamen and the globus pallidus can be grouped together and referred to as the lentiform nucleusA component of the basal nuclei involved in movement regulation.. This group is more involved in communicating with the cerebellum. It directs the output instructions from the basal nuclei to the primary motor cortex.

The cerebral cortexThe outermost layer of the brain, responsible for higher-order thinking and processing. uses the glutamate neurotransmitter to excite the basal nuclei by inputting intentions of movement.  It’s almost like the cerebral cortex is saying, “I’d like to make this movement.” Then it asks, “Tell me how to do it.”  At the same time, the substantia nigra of the midbrain is using dopamine to control the basal nuclei.  When dopamine receptorsProteins located on the surface or inside cells that bind specific molecules (e.g., neurotransmitter of post-synaptic cells in the basal nuclei are not adequately stimulated, some parts of the basal nuclei do not receive enough stimulation. Consequently, they are under-stimulated. Other parts can become over-stimulated. This results in the various symptoms of Parkinson’s.  

The rigidity of Parkinson’s is associated with parts of the thalamus becoming overactive and inhibiting the globus pallidus.  Alternatively, the tremor of Parkinson’s is linked to overactivity of the globus pallidus. This causes the thalamus to allow unnecessary movements, such as a tremor.  

Body movement is not the only brain function affected by Parkinson’s. This occurs despite the staging scale being based on the loss of motor function.  Autonomic functions of the hypothalamusA small but vital brain region controlling hormones, temperature, and autonomic functions. are affected by the loss of dopamine.  Neurons lose the ability to communicate, disrupting negative feedbackA control mechanism that reverses a change in the body to maintain homeostasis.feedback loopsBiological mechanisms that regulate homeostasis by responding to changes. for set points. These include body temperature, thyroid hormone (TH): Includes T3 and T4, regulating metabolism. levels, and solutes in the blood.  The frontal lobeThe brain region responsible for decision-making, personality, and voluntary movements. does not receive the conscious awareness of thirst and hunger. Therefore, it cannot induce drinking or eating.  The limbic systemA group of brain structures responsible for emotions and memory. reduces in function from the loss of dopamine. Emotional expression becomes difficult to manage. This results in depression and anxiety not characteristic of the patient.  Similar to Alzheimer’s patients suffering from a sundowning episode, Parkinson’s patients can present as confused and dehydrated.  

Medications

There are several types of medications used to manage Parkinson’s. Most of these do not cross the blood-brain barrierA selective barrier that prevents harmful substances from entering the brain. and are aimed at conserving the dopamine that is already present.  Other drugs can cross the blood-brain barrier and actually increase the amount of dopamine able to be produced.

1. Block the breakdown action of MAO-B, the enzyme that degrades dopamine. These drugs are selegiline (Eldepryl, Zelapar) and rasagiline (Azilect), which are also neuroprotective and can slow disease progression.
2. Mimic dopamine and bind to the receptors on the post-synaptic cell. These drugs include pramipexole (Mirapex), and ropinirole (Requip), and apomorphine (Apokyn) and are called dopamine agonists
3. Replace missing dopamine in the brain. The drug levodopa helps with movement problems of tremor, stiffness, slowness, and walking. Levodopa is combined with carbidopa (Sinemet). This combination ensures that levodopa is converted to dopamine in the brain. It prevents conversion in the intestine or blood. Different from the other drugs that try to conserve dopamine, Levodopa crosses the blood-brain barrier and is converted into dopamine.
4. Optimize delivery of Levodopa to the brain by blocking COMT. COMT breaks down dopamine in the digestive system. This process allows a steady supply of Levodopa to reach the bloodstream. These drugs include tolcapone (Tasmar) and entacapone (Comtan).
5. Reduce activity of the neurotransmitter acetylcholinealso know as ACh A neurotransmitter that stimulates muscle contraction. at the neuromuscular junctionThe connection between a motor neuron and a muscle fiber.. These drugs reduce tremor and include trihexyphenidyl (Artane) and benztropine (Cogentin).

Our Patient

Seventy-year-old Russell Johnson was diagnosed with Parkinson’s disease three years ago.  Russell currently has stage 3 Parkinson’s disease.  Russell experiences difficulty walking and occasional loss of balance.  He tends to walk hunched over to one side and shuffle his feet.  Russel claims that he has trouble “starting and stopping.”  Russel began to have resting tremors about 1 year ago.  He noticed this on one side at first, but he now has bilateral tremors in his hands.  

Russell has also been experiencing problems with swallowing and sometimes has slurred speech.  His grandchildren have noticed that he has “stoneface” where he doesn’t change his expression to match his spoken emotion.  Russell is often dehydrated with very concentrated urineThe liquid waste excreted by the kidneys., although he never complains of being thirsty.  Last summer he noted that he did not sweat. It was quite hot and his air conditioning did not work.

At first, Russell’s doctors gave him a combination of selegiline and Mirapex.  Both these drugs encourage the use of dopamine which is already naturally produced.  Selegiline is an MAO inhibitor.  Monoamine oxidase (MAO) is the enzyme that breaks down dopamine. Mirapex is a dopamine agonist that mimics dopamine.    Both these drugs can increase the amount of dopamine in the synapseThe junction between two neurons where communication occurs.. They cannot artificially increase the amount of dopamine made by the brain.  As those drugs became less effective, Russell was given Levodopa.  Also known as L-dopa, it is a precursor to dopamine that has been used with Parkinson’s patients since the 1960s.  L-dopa crosses the blood-brain barrier and is readily converted to dopamine. 

Russell will continue to take the Levodopa for as long as it is effective.  This could be up to ten years or more.  Despite medication, however, the effects of Parkinson’s disease gradually worsen and the Levodopa becomes less effective at curtailing the symptoms.  Eventually, alternative drugs will have to be used to help slow the progression of the disease.