Basal Ganglia/Parkinson's

Basal ganglia

Group of deep gray matter nuclei involved in modulation of movement

Basal ganglia main nuclei

Caudate nucleus

Striatum

Caudate plus putamen and serves as the main input structure of the basal ganglia

Lenticular (lentiform) nucleus

Putamen plus globus pallidus and appears lens-shaped

Globus pallidus interna (GPi)

Primary output nucleus of the basal ganglia to the thalamus

Globus pallidus externa (GPe)

Intermediate nucleus involved in indirect pathway modulation

Substantia nigra pars compacta (SNpc)

Dopaminergic nucleus providing dopamine input to the striatum

Substantia nigra pars reticulata (SNr)

Output nucleus functionally similar to GPi

Subthalamic nucleus (STN)

Excitatory nucleus that increases inhibitory output of the basal ganglia

Basal ganglia function

Modulates movement initiation and scaling rather than directly producing movement

Basal ganglia connectivity

Receives major input from cerebral cortex and sends output to thalamus

Parallel basal ganglia loops

Motor

Motor loop of basal ganglia

Regulates voluntary movement execution

Direct pathway

Pathway that decreases inhibitory output from basal ganglia to promote movement

Indirect pathway

Pathway that increases inhibitory output from basal ganglia to suppress movement

Balance of pathways

Normal movement depends on balance between direct and indirect pathways

Direct pathway mechanism

Cortical excitation of striatum inhibits GPi/SNr leading to thalamic disinhibition

Indirect pathway mechanism

Striatal inhibition of GPe leads to STN excitation of GPi/SNr increasing inhibition of thalamus

Role of dopamine in basal ganglia

Dopamine promotes movement by modulating direct and indirect pathways

D1 dopamine receptors

Located on direct pathway neurons and stimulate movement via excitatory effects

D2 dopamine receptors

Located on indirect pathway neurons and promote movement by inhibiting the indirect pathway

Effect of dopamine loss

Reduced movement due to decreased direct pathway activity and increased indirect pathway activity

Parkinson’s disease

Neurodegenerative hypokinetic disorder caused by loss of dopaminergic neurons in SNpc

Core motor features of Parkinson’s disease

Bradykinesia

Bradykinesia

Slowness of movement and difficulty initiating movement

Resting tremor

Tremor present at rest that improves with voluntary movement

Rigidity

Increased muscle tone with resistance to passive movement

Postural instability

Impaired balance leading to falls in later disease

Parkinsonian gait

Shuffling gait with reduced arm swing

Micrographia

Abnormally small handwriting seen in Parkinson’s disease

Pathology of Parkinson’s disease

Degeneration of SNpc neurons with depigmentation of substantia nigra

Lewy bodies

Cytoplasmic inclusions composed of misfolded alpha-synuclein protein

Alpha-synuclein

Presynaptic protein whose aggregation is implicated in Parkinson’s disease toxicity

Timing of motor symptoms

Motor signs appear after ~60% nigral neuron loss and ~80% striatal dopamine loss

Non-motor symptoms of Parkinson’s disease

Constipation

REM sleep behavior disorder

Prodromal Parkinson’s disease feature with dream enactment

Parkinson’s disease risk factors

Older age

Protective factors for Parkinson’s disease

Smoking

Levodopa

Most effective treatment for Parkinson’s disease and precursor to dopamine

Carbidopa

AADC inhibitor given with levodopa to reduce peripheral metabolism and side effects

Levodopa mechanism

Crosses blood-brain barrier and is converted to dopamine in the brain

Levodopa side effects

Nausea

Wearing-off phenomenon

Return of symptoms as levodopa effect diminishes before next dose

Dyskinesias

Involuntary movements associated with long-term levodopa use

COMT inhibitors

Medications that prolong levodopa and dopamine action by blocking metabolism

Entacapone

Peripheral COMT inhibitor used to reduce wearing-off

Tolcapone

Central and peripheral COMT inhibitor with limited use due to hepatotoxicity risk

Opicapone

Once-daily peripheral COMT inhibitor with favorable side-effect profile

MAO-B inhibitors

Medications that reduce dopamine breakdown in the brain

Examples of MAO-B inhibitors

Selegiline

Dopamine agonists

Medications that directly stimulate dopamine receptors

Examples of dopamine agonists

Pramipexole

Advantages of dopamine agonists

Lower risk of dyskinesias and delayed motor complications

Side effects of dopamine agonists

Impulse control disorders

Advanced Parkinson’s therapies

Deep brain stimulation

Deep brain stimulation (DBS)

Surgical treatment targeting STN or GPi to improve motor symptoms

Limitations of current treatments

Treat symptoms but do not slow disease progression