Parkinson's Disease: The Shaking Palsy

What is Parkinson's Disease?

Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily affecting movement. It results from the death of dopamine-producing neurons in a brain region called the substantia nigra. By the time symptoms appear, 60-80% of these neurons have already been lost.[4]

While known for tremor, Parkinson's is much more than a movement disorder. It affects mood, cognition, sleep, autonomic function, and quality of life in profound ways.

Discovery: James Parkinson's Essay (1817)

In 1817, London physician James Parkinson published "An Essay on the Shaking Palsy," a remarkably accurate description based on just six patients, some of whom he had only observed on the street.[1]

He described the "involuntary tremulous motion, with lessened muscular power, in parts not in action... with a propensity to bend the trunk forwards, and to pass from a walking to a running pace."

Parkinson's careful clinical observation established the condition as a distinct entity. French neurologist Jean-Martin Charcot later refined the description in the 1870s, adding rigidity and distinguishing it from other tremor disorders. Charcot named it "Parkinson's disease" in honor of its discoverer.

Understanding the Brain

The substantia nigra ("black substance") gets its name from the dark pigment in its dopamine-producing neurons. These neurons project to the striatum, forming the nigrostriatal pathway crucial for coordinating movement.

Dopamine acts as a neurotransmitter, modulating the complex circuitry of the basal ganglia. When dopamine is depleted, this circuitry becomes unbalanced, leading to the characteristic motor symptoms.

The pathological hallmark of Parkinson's is the Lewy body, clumps of misfolded alpha-synuclein protein inside neurons. These aggregates spread through the brain in a predictable pattern, explaining why symptoms evolve over time.

Causes and Risk Factors

Most Parkinson's cases are "idiopathic" (cause unknown). It likely results from a combination of:

• Genetics: Mutations in genes like LRRK2, SNCA, Parkin increase risk
• Environment: Pesticide exposure, rural living, well water
• Aging: The strongest risk factor; rare before age 50
• Protective factors: Caffeine, smoking (paradoxically), exercise

Non-Motor Symptoms

Often more disabling than tremor, non-motor symptoms include:

• Depression and anxiety: Present in ~50% of patients
• Cognitive impairment: Executive dysfunction; dementia in late stages
• Sleep disorders: REM sleep behavior disorder, insomnia, daytime sleepiness
• Autonomic dysfunction: Constipation, urinary issues, orthostatic hypotension
• Hyposmia: Loss of smell; often precedes motor symptoms by years

The Levodopa Revolution (1960s)

The discovery of levodopa transformed Parkinson's treatment and stands as one of the great achievements of neurology.

In the late 1950s, Oleh Hornykiewicz in Vienna discovered that dopamine was severely depleted in the brains of deceased Parkinson's patients.[2] This suggested replacing dopamine might help.

Since dopamine can't cross the blood-brain barrier, researchers tried its precursor, levodopa (L-DOPA). In 1967, George Cotzias demonstrated that high-dose oral levodopa dramatically improved symptoms.[3]

"Patients who had been wheelchair-bound got up and walked. It was like a miracle."

- Oliver Sacks, describing levodopa's effects

Levodopa remains the most effective treatment, but long-term use leads to complications: motor fluctuations ("wearing off") and dyskinesias (involuntary movements).

Modern Treatment

Current management combines multiple approaches:

Medications

• Levodopa/carbidopa: Gold standard; carbidopa prevents peripheral conversion
• Dopamine agonists: Pramipexole, ropinirole, which directly stimulate dopamine receptors
• MAO-B inhibitors: Selegiline, rasagiline, which slow dopamine breakdown
• COMT inhibitors: Entacapone, which extends levodopa's effect

Deep Brain Stimulation

DBS involves implanting electrodes in specific brain regions (subthalamic nucleus or globus pallidus) connected to a pacemaker-like device. High-frequency electrical stimulation modulates abnormal brain activity, reducing motor symptoms and allowing medication reduction.

DBS can dramatically improve quality of life for appropriate candidates, though it doesn't slow disease progression.

The Search for Disease-Modifying Treatments

Current treatments manage symptoms but don't slow neurodegeneration. Research focuses on:

• Alpha-synuclein targeting: Antibodies, small molecules to prevent aggregation
• Gene therapy: Delivering genes to boost dopamine production
• Neuroprotection: Preserving remaining dopamine neurons
• Cell replacement: Stem cell-derived dopamine neurons

Clinical trials are ongoing, but no disease-modifying therapy has yet succeeded.

Living with Parkinson's

Non-pharmacological approaches are crucial:

• Exercise: Strong evidence for benefit; may slow progression
• Physical therapy: Gait training, balance exercises
• Speech therapy: LSVT LOUD for hypophonia
• Support groups: Community and shared experience

With modern treatment, many people with Parkinson's live decades with good quality of life. The disease is serious but not hopeless, and research continues to advance.