507 - Lecture 9: Parkinson's Disease

Learning Objectives for this lecture:

• Describe the cardinal motor and non-motor manifestations of Parkinson disease.

• Explain how degeneration of dopaminergic neurons alters basal ganglia signaling.

• Relate Parkinson disease pathophysiology to clinical manifestations that guide pharmacologic treatment.

What are motor symptoms related to Parkinson’s disease?

• Impairments in the initiation, execution, and coordination of voluntary movement caused by dopamine depletion within the basal ganglia motor circuit

• Acronym TRAP

  • Tremor at rest (pill-rolling)

  • Rigidity in legs, arms, trunk, face

    • Cogwheel rigidity

  • Akinesia or bradykinesia (feeling “sluggish” or “weakness”)

    • Slow speech, low volume (hypophonia)

    • Slowness of movement in both initiation and execution

    • Bradykinesia is required for the clinical diagnosis of Parkinson disease

  • Postural instability

    • Forward leaning •Imbalance, falls •Shuffling, short-stepped gait

What is Parkinson’s disease?

Chronic, progressive, irreversible neurological disorder affecting mostly the extrapyramidal motor system in the CNS

• 2nd most common neurodegenerative movement disorder (Alzheimer’s disease is 1st)

What are the nonmotor symptoms of Parkinson’s disease?

• Do not primarily affect movement but are a result from dysfunction of dopaminergic and non-dopaminergic pathways

• Neurological, cognitive, psychiatric, autonomic, sensory, and sleep-related manifestations that occur due to neurodegeneration extending beyond the basal ganglia and substantia nigra

Describe tremors of Parkinson’s disease:

• Resting tremor

• Often described as “pill rolling”

• Presenting symptom in ~70% of patients with PD

• Begins intermittently and unilaterally

• Often begins with a feeling of internal tremulousness in limbs that is not observable

• Can progress to tremor with movement, but always more severe at rest

• Worsened by emotional excitement, anxiety, and stress

Describe rigidity of Parkinson’s Disease:

• Occurs with passive movement around a joint

  • Cogwheel rigidity

• Often begins unilaterally on the same side as tremor

• Decreased arm swing with walking

What is cogwheel rigidity?

Ratchety pattern of resistance and relaxation as the examiner moves the limbs through its full range of motion

What is akinesia or bradykinesia?

• Generalized slowness of movement

• Most difficult effect of PD for suffers to describe

  • “Weakness, incoordination, tiredness”

• Decreased dexterity of the fingers

• Difficulty buttoning shirts, tying shoes

• Dragging the legs, shorter steps (shuffling), feeling of unsteadiness

• *Required for clinical diagnosis of PD

Desribe postural instability of Parkinson’s Disease:

• Due to impairment of centrally-mediated postural reflexes → Feeling of imbalance

• Tested with the ‘pull test’:

  • Examiner pulls the patient by the shoulders from behind. Normally, can maintain balance by taking one step back

  • Patients with PD, are likely to fall or take multiple steps backwards

• Stooped posture

• Can lead to falls and significant disability (wheelchair bound)

What non-motor symptoms are seen with Parkinson’s disease?

• Cognitive/Psychiatric

  • Cognitive dysfunction and dementia

  • Anxiety

  • Depression, Apathy

  • Fatigue

  • Psychosis/Hallucinations

  • Insomnia

• Autonomic

  • Excessive sweating

  • Dyspnea

  • Orthostasis

  • Sexualdysfunction

  • Dryredskin (seborrhea)

  • Urinary incontinence

  • Constipation

• Sensory/Pain

  • Paresthesia

  • Akathesia (inability to sit still)

  • Loss of smell

  • Diffuse pain

When are non-motor symptoms seen in PD?

They often precede motor symptoms and become increasingly prevalent as disease progresses

Virtually all patients with PD will have non-motor symptoms

Pain, mood disorders, and sleep problems are the most troublesome

In a normal motor circuit, what role does the motor cortex play?

• Initiates voluntary movement

• Sends motor commands to the body

In a normal motor circuit, what role does the basal ganglia play?

• Selects and fine-tunes voluntary movements

• Suppresses unwanted or competing movements

In a normal motor circuit, what role does the thalamus play?

• Relays motor signals from the basal ganglia back to the motor cortex

• Acts as “gatekeeper” for movement

In a normal motor circuit, what role does the substantia nigra pars compacta (SNpc) play?

• Located in the midbrain

• Produces dopamine

• Supplies dopaminergic input to the striatum through nigrostriatal pathway

• Facilitates smooth, coordinated voluntary movement

What is the pathophysiology of Parkinson’s disease?

• Step 1: Loss of Dopaminergic Neurons in Substantia Nigra Pars Compacta (SNpc)

• Step 2: Formation of Lewy Bodies

• Step 3: Progressive Spread of AlphaSynuclein Pathology (Braak Staging)

• Step 4: Mitochondrial Dysfunction and Oxidative Stress

• Step 5: Normal function of the Substantia Nigra (SN)

• Step 6: Direct Pathway (“Go” Pathway)

• Step 7: Indirect Pathway (“Stop” Pathway)

• Final Integrated Mechanism

Describe what happens in Step 1 (Loss of Dopaminergic Neurons in SNpc)

• These neurons normally project to the striatum (caudate nucleus and putamen) through the nigrostriatal pathway

• Dopamine released from SNpc neurons is essential for normal motor control

• PD is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the mid brain

Describe what happens in Step 2 (formation of Lewy bodies)

• Misfolded α-synuclein proteins aggregate into Lewy Bodies (intracellular protein aggregates)

• α-synuclein aggregation:

  • Disrupts normal neuronal function

  • Promotes cellular stress

  • Contributes to neuronal death

• Neuropathologic hallmark of PD

Where are Lewy bodies found/distributed?

• In the substantia nigra, other brain regions, cerebral cortex

• This widespread distribution helps explain both: Motor symptoms and non-motor symptoms

Describe what happens in Step 3 (Progressive Spread of AlphaSynuclein)

Starts at Stage 1: Lower brainstem

• Stage 2: Raphe nuclei

• Stage 3: Substantia nigra

  • This stage is required for classic Parkinson motor symptoms

• Stage 4: Mesocortex, thalamus

• Stage 5: Neocortex; prefrontal cortex

• Stage 6: Entire neocortex

What is the clinical significance of progressive spreading of alpha synuclein?

• Early stages may be asymptomatic

• Motor symptoms emerge when pathology reaches substantia nigra

• Later cortical involvement produces many non-motor manifestations

Describe what happens in Step 4 (oxidative stress and mitochondrial dysfunction)

• Environmental toxins associated with PD (examples)

  • Rotenone

    • Pesticide → Inhibits mitochondrial Complex I

  • Paraquat

    • Herbicide → Generates oxidative stress

  • Manganese —> Neurotoxic metal

  • MPTP

    • Meperidine contaminant

    • Complex I inhibitor

What is the result of oxidative stress and mitochondrial dysfunction?

ATP depletion, excess reactive oxygen species, oxidative damage, death of dopaminergic neurons

What is the normal function of the substantia nigra (Step 5)?

Normal role

• Supplies dopamine to the striatum

• Regulates voluntary motor activity

• Supports movement with intention In PD

• Participates in certain cognitive functions such as spatial learning

How does the substantia nigra function in Parkinson’s disease?

Neurodegeneration of the SNpc leads to dopamine deficiency within the basal ganglia circuit

Describe the direct pathway (“go” pathway) of Parkinson’s disease (Step 6)

• Circuit

  • SNpc → Striatum (D1 receptors) → GPi/SNpr → Thalamus → Cortex

• Dopamine effect

  • Dopamine stimulates D1 receptors

• Result:

  • Promotes thalamic activity

  • Increases cortical motor output

  • Facilitates movement

• In PD

  • Less dopamine

  • Less D1 stimulation

  • Less activation of the direct pathway

  • Less movement

Describe the indirect pathway (“go” pathway) of Parkinson’s disease (Step 7)

• Circuit

  • SNpc → Striatum (D2 receptors) → GPe → STN → GPi/SNpr → Thalamus → Cortex

• Dopamine effect

  • Dopamine suppresses activity of the indirect pathway through D2 receptors

• Result

  • Reduces movement suppression

  • Facilitates movement

• In PD

  • Loss of dopamine

  • Increased indirect pathway activity

  • Increased inhibition of the thalamus

  • Reduced cortical stimulation

  • Reduced movement

Summarize the final integration of steps 1-7 in normal patients:

• Dopamine from the SNpc

  • Activates D1 receptors → stimulates the direct pathway

  • Activates D2 receptors → suppresses indirect pathway

  • Both actions increase thalamocortical signaling and promote movement

Summarize the final integration of steps 1-7 in patients with Parkinson’s disease:

• Alpha-Synuclein accumulates → Lewy bodies form

• Oxidative stress and mitochondrial dysfunction contribute to neuronal death

• Dopaminergic neurons in the SNpc degenerate

• Dopamine delivery to the striatum falls

• Direct pathway activity decreases

• Indirect pathway activity increases

• Thalamic output to the motor cortex decreases

• Voluntary movement becomes impaired

What is the result of decreased dopamine in PD?

↓ dopamine → ↓ direct pathway + ↑ indirect pathway → ↓ thalamocortical stimulation → bradykinesia, rigidity, tremor, and postural instability

What is the relationship between Dopamine-Acetylcholine in Parkinson’s disease?

In PD, there is less Dopamine from Substantia nigra to provide negative feedback to Acetylcholine neurons within Striatum

Increase in what NT is thought to worsen tremors?

Increased Acetylcholine → thought to worsen tremors

What is the relationship between Dopamine-Adenosine_2A in PD?

In PD, less Dopamine from Substantia nigra causes upregulation of Adenosine_2A receptors

Increased A2A Receptors → thought to stimulate the Indirect Pathway → bradykinesia

What is the clinical effect manifestation of dopamine depletion?

Bradykinesia

What is the clinical effect manifestation of increased indirect pathway activity?

Rigidity

What is the clinical effect manifestation of reduced thalamocortical output?

Akinesia

What is the clinical effect manifestation of

What is the clinical effect manifestation of cortical Lewy body spread?

Cognitive decline

What is the clinical effect manifestation of

What is the clinical effect manifestation of brainstem involvement?

Sleep disturbances

What is the clinical effect manifestation of autonomic involvement?

Constipation, orthostasis

What are other types of tremors?

• Resting tremor: occurs in body part that is not fully supported and not voluntarily activated

  • Most common – suggestive of Parkinson disease

• Action tremor: occurs with voluntary muscle contraction

  • Essential tremor

    • Treatment: propranolol, primidone

  • Enhancement of physiologic tremor (most common action tremor)

    • Drug-induced increase adrenergic activity: beta agonist (epinephrine, albuterol), SSRIs, TCAs, levodopa, xanthines (caffeine, theophylline), withdrawal of opioids or alcohol