Parkinson's disease

Disease class: Neurodegenerative diseases

Disease class: Parkinsonian disorders

Also known as 

Hypokinetic rigid syndrome

 

Physiology

• The basal ganglia.

 

Pathophysiology

In a brain with Parkinson's disease, there is a death of cells in the substantia nigra (black substance). These cells are specialised in producing dopamine. Without them, the ability of the basal ganglia to produce sufficient dopamine is reduced, and the "unlocking" signal is too weak. This means that the inhibitory signals are not sufficiently deactivated, so there is too much inhibition.

Motor inhibition results in bradykinesia (slow movement), akinesia (no movement), resting tremor (rapidly alternating muscle contractions and relaxations), increased muscle tone (constant contraction and tension of all muscles), expressionless facies (lack of facial expression) and more. The motor symptoms are the most famous, as they are easy to recognise, and can progress to complete (but reversible) immobility. This is terrifying for patients, especially those living alone. However, the dysfunction of the basal ganglia affects many circuits, and a large range of neuropsychiatric symptoms often develop.

Many cognitive abilities are impaired including working memory, facial recognition, social inhibition. Sleep is commonly dysfunctional. Depression is common and hallucinations occur in 50%. The disease often results in dementia eventually.

It's not known why there is cell death in the substantia nigra neurons specifically, but there has been a wealth of research into the area. The remaining neurons in the brain of these patients often contain Lewy bodies (clumps of a protein called alpha-synuclein). Certain variants of the gene (SNCA) which encodes this protein have been linked to Parkinson's disease. Other genes associated with Parkinson's disease (such as LRRK2) also encode proteins found in the cytoplasm (cell contents) of neurons.

In a brain which has had destruction of basal ganglia: e.g. pallidotomy, thalamotomy, there is a reduction in inhibition. This reduces the symptoms of Parkinson's disease, but can also cause dyskinesia (purposeless involuntary movements) and ballismus (dramatic involuntary flailing movements of the limbs or face). Damage to the basal ganglia can also cause impaired processing of languages, visuospatial construction and other brain functions. Bilateral (both sided) destruction of basal ganglia components greatly increases the risk of dysfunction, potentially leading to unintelligible speech, apathy, depression and difficulty coordinating the muscles of the head (pseudobulbar palsy).

 

Management

Since inhibition of motor activity is the main concern for most of these patients, treatment is used which reduces the inhibition. Pro-drugs like levodopa (which the body converts to dopamine), and drugs which signal like dopamine (e.g. pramipexole, bromocriptine), can be used to enhance dopaminergic signalling levels in the brain. This helps the basal ganglia to reach the dopamine levels needed to unlock the basal ganglia.

The problem with these treatments is that the dopamine is not being released precisely. This results in dyskinesia (involuntary movements) from unnecessary inhibition of motor signals. Dopamine also has functions elsewhere in the brain, including the mesolimbic pathway. Adding dopamine to these systems can cause psychosis (loss of grasp on reality), impulsive behaviours (such as gambling, drug addiction, excessive spending) and punding (becoming fascinated in pointless activities like disassembling household objects and repeating the activity for hours). These are important side effects of Parkinson's disease treatments.

It's also important to note that dopamine has peripheral effects (the body), not just central effects (the brain). Levodopa is intended to affect the brain but not the peripheral nerves, so any patient given levodopa should be given a drug to block peripheral action (e.g. carbidopa).

In severe cases of Parkinson's disease, neurosurgeons can offer to destroy parts of the basal ganglia to achieve a reduction of inhibition. As described above, this can leave patients with lifelong dyskinesias such as ballismus, or even significant cognitive impairments.