What is Parkinson's disease?

Parkinson's Disease: A Neurodegenerative Movement Disorder

Parkinson's disease is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra, resulting in the cardinal motor symptoms of resting tremor, rigidity, bradykinesia, and postural instability. 1

Pathophysiology and Mechanism

Parkinson's disease (PD) is a synucleinopathy with the following key pathological features:

• Neuronal degeneration: Progressive loss of dopaminergic neurons in the substantia nigra projecting to the striatum

  • Symptoms typically appear after 40-50% of dopaminergic neurons are lost (approximately 5 years after initial neurodegeneration begins) 1

• Lewy body formation: Intracellular protein aggregates composed primarily of:

  • Alpha-synuclein
  • Ubiquitin 1

• Pattern of progression: Lewy body deposition follows a specific pattern:

  1. Initially affects medulla oblongata, pontine tegmentum, and olfactory system
  2. Later involves substantia nigra and other deep gray nuclei (coinciding with clinical symptom onset)
  3. Finally spreads to the cerebral cortex 1

Clinical Presentation

Cardinal Motor Symptoms

• Resting tremor (often asymmetric at onset)
• Rigidity
• Bradykinesia (slowness of movement)
• Postural instability (typically in advanced stages) 1, 2

Non-Motor Symptoms

• Autonomic dysfunction
• Behavioral changes
• Cognitive decline and dementia
• Depression and anxiety
• Sleep disturbances (including REM sleep behavior disorder)
• Constipation
• Hyposmia (reduced sense of smell) 1, 2

Disease Subtypes and Progression

PD is heterogeneous with different clinical subtypes that affect prognosis:

1. Diffuse malignant subtype (9-16% of cases):

   • Prominent early motor and non-motor symptoms
   • Poor response to medication
   • Faster disease progression 2

2. Mild motor-predominant subtype (49-53% of cases):

   • Mild symptoms
   • Good response to dopaminergic medications
   • Slower disease progression 2

3. Intermediate subtype: Features between the above two types 2

Disease progression is typically faster in patients with predominant rigidity and bradykinesia compared to those with predominant tremor 3.

Nutritional Considerations

PD patients are at increased risk for malnutrition and weight changes:

• 15% of community-dwelling PD patients are malnourished
• 24% are at medium or high risk of malnutrition 1
• Weight loss may be present at diagnosis and is associated with disease progression
• Increased energy expenditure from dyskinesias and rigidity is not fully compensated by increased energy intake 1

Diagnosis

Diagnosis is primarily clinical, based on history and examination findings:

• Clinical history: Presence of cardinal motor symptoms and prodromal features
• Physical examination: Demonstration of bradykinesia with tremor, rigidity, or both
• Dopamine transporter SPECT: Can improve diagnostic accuracy when parkinsonism is uncertain 2
• I-123 ioflupane SPECT/CT: Valuable for differentiating Parkinsonian syndromes from essential tremor and drug-induced tremor 1
  • A normal scan essentially excludes Parkinsonian syndromes
  • Shows decreased radiotracer uptake in the striatum, usually progressing from putamen to caudate nuclei

Treatment Approaches

Pharmacologic Management

1. Dopamine replacement therapy:

   • Levodopa (combined with carbidopa): The most effective treatment for motor symptoms
     • Carbidopa inhibits peripheral decarboxylation of levodopa, allowing more levodopa to reach the brain
     • Reduces the amount of levodopa required by about 75%
     • Increases plasma half-life of levodopa from 50 minutes to about 1.5 hours 4
   • Dopamine agonists: Option for initial treatment, can delay onset of motor complications but less effective than levodopa for controlling motor symptoms 5

2. Adjuvant therapies for advanced disease:

   • Catechol O-methyltransferase (COMT) inhibitors
   • Monoamine oxidase-B (MAO-B) inhibitors 5

3. Management of non-motor symptoms:

   • Selective serotonin reuptake inhibitors for psychiatric symptoms
   • Cholinesterase inhibitors for cognitive symptoms 2

Advanced Therapies for Complicated Disease

For patients with medication-resistant tremor, "off periods," or dyskinesias:

• Deep brain stimulation of the subthalamic nucleus
• Levodopa-carbidopa enteral suspension therapy 2, 5

Non-pharmacologic Approaches

• Regular exercise
• Physical therapy
• Occupational therapy
• Speech therapy 2

Important Clinical Considerations

• Long-term levodopa complications: After 5-10 years of treatment, most patients develop:

  • Motor fluctuations ("wearing-off" phenomenon)
  • Dyskinesias (involuntary movements) 6

• Treatment-resistant symptoms: Disease progression leads to development of:

  • Dementia
  • Autonomic dysfunction
  • Postural instability
  • These symptoms typically do not respond to levodopa therapy 6

• Nutritional monitoring: PD patients should undergo regular monitoring of:

  • Body weight changes
  • Vitamin D, folic acid, and vitamin B12 status 1

Disease-Modifying Therapies

Currently, there are no approved disease-modifying treatments that can slow or halt the progression of PD. All current therapies are symptomatic 2, 6. Significant research efforts are directed toward developing neuroprotective agents that might modify disease progression 3.