Think of the motor cerebral cortex as the “command center” that directly (via the cerebrospinal pathway) stimulates the lower motor neurons in the ventral gray matter of the spinal cord. The following “loops” help the command center out:
-Basal ganglia-thalamic-cortical loop;
-Cerebellar-thalamic-cortical loop. 

-Ataxia gait (wide stance, side way jerking back and forth for balance, unability to walk on straight line);
-Intention tremor: intention tremor increases as an extremity approaches the endpoint of deliberate and visually guided movement (hence the name intention tremor). When experiencing an intention tremor, one often overshoots or undershoots their target. 

What are the two loops by which the basal ganglia controls movement? Which one involves recurrent excitation of cortical motor regions? Recurrent inhibition of cortical motor regions? 

-The direct loop results in recurrent excitation of cortical motor regions via thalamus;

-The indirect loop results in recurrent inhibition of cortical motor regions via thalamus. 

Which nucleus in the basal ganglia is directly involved in Parkinson’s disease? What neurotransmitter is produced by the neurons of this nucleus? What determines whether the release of this neurotransmitter in other nuclei within the basal ganglia is excitatory or inhibitory? What are the two nuclei onto which this neurotransmitter is released? 

-Substantia nigra compacta (SNc);
-Dopamine;
-Which dopamine receptor resides on the membrane of the target neurons within the basal ganglia: Stimulation of the D1 receptor will result in excitation, and stimulation of D2 will result in inhibition;
-The putamen and the caudate nuclei. 

-D1
-An increase in thalamocortical excitation. 

-D2
-Inhibiting the indirect pathway. Inhibition of the indirect loop will result in increasing excitation of the motor cortex.

An overall effect of increasing excitation of the motor cortex by exciting the direct loop and inhibiting the indirect loop.

Degeneration (neuronal loss and depigmentation) in the substantia nigra. 

When considering the direct loop, what is the effect of the depletion of dopamine in the SNc? When considering the indirect loop what is the effect? 

-decreased cerebral cortical excitation over the thalmocortical projection fibers;

-increases the putamen and caudate inhibition of the thalamus which results in allowing the indirect loop to inhibit the cortical motor regions.

F, Masked face. 

A, Bradykinesia

E, Parkinsonian gait

D, Resting tremor

B, Rigidity

C, Postural instability

When considering the neuropsychiatric disturbances, what is the Parkinsonian patient at risk for that is accompanied with behavior and mood alterations such as depression, apathy, and anxiety? 

Dementia

Besides the deficits caused by depletion of dopamine in the SNc, what is the second major cause of behavioral alterations? 

The medications used to manage the disease. 

Why is levodopa (L-DOPA) rather than dopamine used in the treatment of Parkinson’s disease? Initially, why was large doses of L-DOPA needed to treat the disease? What were the side-effects of large doses of L-DOPA? 

-The L-DOPA, unlike dopamine, is able to cross the blood-brain barrier and enter neurons in the substantia nigra.
-Because in the circulatory system L-DOPA was rapidly metabolized by the enzyme dopa- decarboxylase (DDC);

-Nausea, dyskinesias (motor conditions associated with Parkinson’s Disease), and joint stiffness. 

What role does a dopa-decarboxylase (DDC) inhibitors play in the treatment of Parkinson’s disease? Same for catechol-O-methyl transferase (COMT) inhibitors? 

-Inhibiting DDC using a DDC inhibitor kept the levels of Levodopa higher for a longer period of time allowing the reduction of Levodopa dose by 70%. The lower dosage of Levodopa reduced the severity of side-effects significantly;
-However, when DDC is inhibited another enzyme, catechol-O-methyl transferase (COMT), takes over the breakdown of Levodopa to 3-O-methyldopa (3-OMD. Consequently, COMT inhibitors were recently developed as a way of further improving the delivery of Levodopa to the brain 

Given the answers to questions #18 and #19, what three drugs make up levodopa preparations. 

L-DOPA, DDC inhibitors, and COMT inhibitors.

Define “on state” and “off state” in terms of the patients response to Levodopa preparations. 

“On state” to a period or phase of time when the patient is experiencing a good response to medications with few symptoms; and “off state” is a phase of time when the patient is not responding to medication in that they are having significant motor defects and associated symptoms.

What are the two approaches used to extend the time of either no doses or low doses of levodopa preparations? 

The two approaches to extend the time of low doses of levodopa preparations are the use of pharmaceutical alternatives and exercise. 

What is the main reason pharmaceutical alternatives are used in the treatment of Parkinson’s Disease? Explain the action of Dopamine agonists and monoamine oxidase- B (MAO-B) inhibitor. 

-Pharmaceutical alternatives initial therapy for motor symptoms with the aim of delaying the use of levodopa preparations or keeping levodopa preparations at low dosage;

-Dopamine agonists bind to dopaminergic post-synaptic receptors and, therefore, have similar effects at L-DOPA;

-Monoamine oxidase-B (MAO-B) inhibitor specifically acts by decreasing the metabolism of dopamine within the cells of the basal ganglia, thereby increasing dopamine’s availability.

What has research demonstrated when comparing an exercise program under physiotherapist supervision vs self-supervised home program? 

An exercise program under physiotherapist supervision was found to be more effective at improving activities of daily living, motor, mental, emotional function and general health quality in patients with Parkinson’s disease compared with a self-supervised home program. 

In this stage levodopa preparations are first prescribed.  Exercise prescription should be adjusted to the patient’s capabilities and capacities, but continued if the patient is willing. 

Exercise should be continued as the primary treatment, with dopamine agonist and MAO-B inhibitors either initiated or continued. 

Physical movements become much slower and major impairments in walking straight and standing are present. Falling down is more common increasing the risk of injuries, especially in the elderly. Generalized dysfunction is moderately severe. 

Symptoms are severe and the individual is unable to complete day-to-day tasks and walking is little, if at all. For these reasons, patients are unable to live alone and are generally confined to a wheelchair. Surgery (e.g., deep brain stimulation therapy) is an option at this stage to alleviate some of the symptoms, but only in young and healthy individuals. A paucity of research exists to determine the feasibility, safety, and outcomes of exercise. 

In Dr. Pitetti’s opinion, exercise should be the primary treatment approach. However, medications may be started during this stage and typically involves the L-DOPA alternatives such as dopamine agonists and monamine oxidase-B (MAO-B) inhibitors. 

Symptoms are generally mild and only cause minor inconveniences in day-to-day living. Minor tremors or shaking occurs, but is unilateral, affecting only one side of the body. Along with minor tremors, an individual's posture and balance become poorer and abnormal facial expressions become apparent. Overall, this stage causes no major problems and can last for several years. 

Bilateral symptoms develop in which both sides of the body are affected. Disability is minimal and daily tasks can still be performed, but are much harder to complete. Walking and balance problems become more severe with further declines in posture.