Case 10: Shelley Clerke - Parkinson's Disease

Basal Ganglia: Location

Nuclei group under cortex

Throughout…

• Telencephalon (cerebrum)

• Diencephalon

• Mesencephalon (midbrain)

Basal Ganglia: Parts

Striatum

Lentiform nucleus

Subthalamic nucleus

Substantia nigra

Basal Ganglia: Striatum

Caudate nucleus + putamen

• Motor excitatory

• Motor inhibitory

Basal Ganglia Striatum: Motor Excitatory

Increase motor activity

Inhibit Gpi

Contain D1 receptors (dopamine-activated)

NT:

• GABA

• Substance P

Basal Ganglia Striatum: Motor Inhibitory

Decrease motor activity

Inhibit Gpe

Contain D2 receptors (dopamine-inhibited)

NT: GABA

Basal Ganglia: Lentiform Nucleus

Globus pallidus + putamen

• Globus pallidus internus (Gpi)

• Globus pallidus externus (Gpe)

Basal Ganglia Lentiform Nucleus: Gpi

Inhibit thalamus = Decrease motor activity

NT: GABA

Basal Ganglia Lentiform Nucleus: Gpe

Inhibit subthalamic nucleus = Increase motor activity

NT: GABA

Basal Ganglia: Subthalamic Nucleus

Stimulate Gpi + pars reticularis = Decrease motor activity

NT: Glutamate

Basal Ganglia: Substantia Nigra

Pars compacta

Pars reticularis

Basal Ganglia Substantia Nigra: Pars Compacta

Stimulate motor excitatory striatum + inhibit motor inhibitory striatum = Increase motor activity

NT: Dopamine

Basal Ganglia Substantia Nigra: Pars Reticularis

Inhibit thalamus = Decrease motor activity

Cortico-Basal Ganglia-Thalamo-Cortical Loop (CBGTC)

Neuronal circuit between brain cortex, basal ganglia, thalamus

Function:

• Initiate movement

• Control skeletal muscles + posture

Pathways: Modulated by dopamine

• Direct

• Indirect

Direct Pathway

Excitatory = Increase motor activity

• D1 receptors = Upregulate direct pathway

1. Motor cortex activation = Release glutamate = Stimulate striatum = Release GABA
   ALSO
   Subthalamic nucleus stimulate substantia nigra = Release dopamine = Bind striatum D1 receptors

2. Inhibit Gpi = Inhibit GABA release = Thalamus disinhibition = Release glutamate

3. Stimulate premotor cortex = Muscle activation = Increase movement

Indirect Pathway

Inhibitory = Decrease motor activity

1. Motor cortex activation = Release glutamate = Stimulate striatum = Release GABA

2. Inhibit Gpe = Decrease GABA release = Subthalamic nucleus disinhibition = Release glutamate

3. Stimulate substantia nigra + Gpi = Gpi release GABA = Inhibit thalamus

4. Decrease excitatory output → Motor cortex = Muscle deactivation = Decrease movement

Indirect Pathway Modulation

Increase motor activity

• D2 receptors = Downregulate indirect pathway

1. Substantia nigra release dopamine (tonic activation) = Bind striatum D2 receptors

2. Inhibit GABA release = Gpe disinhibition = Increase GABA release

3. Inhibit subthalamic nucleus = Decrease Gpi stimulation

4. Thalamus disinhibition = Release glutamate = Increase movement

Basal Ganglia Dysfunction Presentation

Motor deficits

Cognitive deficits

Behavioural deficits

Basal Ganglia Dysfunction: Motor Deficits

Bradykinesia/akinesia

Rigidity

Resting tremor

Dystonia

Tics

Chorea: Irregular involuntary movements migrating between body segments

Basal Ganglia Dysfunction: Cognitive Deficits

Impaired planning + problem-solving

Decreased working memory

Attention deficits

Learning impairments

Basal Ganglia Dysfunction: Behavioural Deficits

Anxiety

Depression

OCD

Parkinson’s Disease (PD): Description

Progressive neurodegenerative condition causing dopaminergic neuron depletion in basal ganglia

PD: Epidemiology

2nd most common neurodegenerative disorder (after Alzheimer)

Risk factors…

• Genetic

• Environmental

  • Exposure to manganese

• Diet

  • Low vit D

  • High Fe

• Obesity

• TBI

PD: Etiology

Idiopathic

Genetics

PD Etiology: Genetics

Alpha-synuclein (SNCA): Protein regulating NT release + synaptic function

Glucocerebrosidase (GBA): Lysosomal enzyme

Dardarin: Leucine-rich repeat kinase 2 (LRRK2) enzyme/gene

• Common in autosomal dominant

Parkin: Protein encoded by PRKN gene

• Common in autosomal recessive

PD: Secondary Parkinsonism

Neurological disorders causing PD symptoms

Secondary Parkinsonism: Etiology

Drugs

Metabolic disorders

Toxins

CNS diseases

Secondary Parkinsonism: Drugs

Most common cause

Antidopaminergics

• Antipsychotics

• Antiemetics

• CCBs

• Amiodarone

• Valproate

• Lithium

MPTP: Damage substantia nigra

Secondary Parkinsonism: Toxins

Manganese

CO

Secondary Parkinsonism: CNS Diseases

Cerebrovascular disease

Infections

Huntington disease

PD: Pathophysiology

Motor symptoms

1. Defective protein + debris clearance = a-synuclein/protein aggregation (Lewy bodies) + oxidative stress = Neuroinflammation

2. Progressive dopaminergic neuron degeneration in substantia nigra (basal ganglia) + locus coeruleus (pons) = Dopamine deficiency

3. Decrease D1/2 receptor binding = Impaired transmission to thalamus + motor cortex = Motor symptoms

Depressive symptoms

• Serotonin + noradrenaline depletion

Dyskinesia:

• Increased ACh

PD: Clinical Presentation

Preclinical

Clinical

PD Clinical Presentation: Preclinical

No motor signs

Constipation

Ansomina: Loss of smell

Sleep disturbances

Mood disorders

PD Clinical Presentation: Clinical

Motor:

• Unilateral onset → Contralateral

• Asymmetrical

• Parkinsonism:

  • Bradykinesia

  • Resting tremor

    • Decrease with voluntary movements

    • Increase with stress

  • Joint rigidity

    • Cogwheel Rigidity: Increased muscle tone + resting tremor = Passive stretch cause jerking motion

  • Unstable posture

    • Increase fall

    • Stooping

  • Parkinsonism gait: Shuffling + quick/short steps

  • Micrographia: Decreased handwriting size

Nonmotor:

• Autonomic

  • Orthostatic hypotension

  • Urinary urgency

  • Impaired sexual function

• Neuropsychiatric

PD: Investigations

Physical exam

Genetic testing

Imaging

Levodopa challenge test

PD Investigations: Physical Exam

Clinical diagnosis

Neurological exam

Parkinsonism

PD Investigations: Imaging

Not routine

MRI: Nonspecific putamen atrophy

PD Investigations: Levodopa Challenge Test

Not routine

Evaluate motor symptoms before, during, after oral levodopa + decarboxylase inhibitor

• Levodopa: Dopamine precursor

  • Conversion catalyzed by decarboxylase

Positive = Levodopa relieve symptoms

PD: Management

Nonpharmacologic

Pharmacologic: Start when symptoms cause functional impairment

Deep brain stimulation

PD Management: Nonpharmacologic

Physical therapy

Exercise

Fall prevention

Nutrition

Sleep hygiene

Advance care planning

• Palliative care as needed

PD Management: Pharmacologic

Levodopa + Carbidopa (L-DOPA)

Dopamine agonist

MAO-B inhibitors

Anticholinergics

NMDA antagonists

COMT inhibitors

PD Pharmacologics: Levodopa + Carbidopa (L-DOPA)

MOA: Decarboxylase convert levodopa to dopamine = Increase dopamine binding

• Carbidopa: Decarboxylase inhibitor

  • Prevent conversion outside CNS

Indications: Initial treatment

Adverse Effects:

• Increase dyskinesia over time

• Honeymoon Period: More benefits in early phase

PD Pharmacologics: Dopamine Agonist

Ex: Pramipexole, ropinirole, apomorphine

MOA: Increase dopamine receptor stimulation

Indications: Younger patients

Adverse Effects: Psychiatric impairment

PD Pharmacologics: MAO-B Inhibitors

Ex: Selegiline

MOA: Inhibit monoamine oxidase (MAO)-B = Decrease dopamine metabolization in brain

Indications: Mild disease

Adverse Effects: Worsen dyskinesia

PD Pharmacologics: Anticholinergics

Ex: Benztropine, trihexyphenidyl

MOA: Inhibit excitatory cholinergic neurons = Decrease ACh concentration

Indications: Younger patients with tremor

Adverse Effects: Anticholinergic effects

• Psychiatric symptoms

• Urinary retention

PD Pharmacologics: NMDA Antagonists

Ex: Amantadine

MOA:

• Inhibit NMDA receptor

• Increase dopamine release + decrease dopamine reuptake

Indications:

• Short-term treatment for mild symptoms

• Levodopa-induced dyskinesia

Adverse Effects:

• Delirium

• Dizziness

• Anxiety

PD Pharmacologics: COMT Inhibitors

Ex: Entacopone

MOA: Inhibit catechol-o-methyltransferase (COMT) = Decrease peripheral L-DOPA metabolism = Increase bioavailability

Indications: Levodopa-induced akinesia

PD Management: Deep Brain Stimulation

Implant stimulating electrodes targeting subthalamic nucleus or Gpi = Decrease signalling = Increase motor activity

Indications: Severe motor symptoms

PD: Complications

Falls + fractures

Aspiration pneumonia

PD: Prognosis

Decreased life expectancy (7-14 years after diagnosis)