Parkingson’s disease
Theoretical background
Chronic Progressive Degenerative Brain Disorder
Fastest growing neurological disorder
Second-most common neurodegenerative disorder
▪ 2-3% of population ≥65 years of age
Cause: degeneration of dopamine-producing cells in the
substantia nigra of the basal ganglia
Effect: typical motor symptoms, non-motor features and neurobehavioral abnormalities
Epidemiology
Estimated global incidence: 5 to 230 new cases per 100,000 individuals yearly.
Rare before age 50
Incidence 5 to 10-fold from ages 60-90
Global prevalence estimated 0.3%
▪ Increases to >3% in >80 years
Usually: onset between ages 60-70
Genetic variant: Young Onset PD
▪ 5-20% of persons w/ PD
Male:Female distribution ± 1.5:1
Most cases: idiopathic (no known cause)
Most likely a combination of factors:
• Age
• Environmental (toxins, pesiticides, insecticides: rotenone, paraquat, MPTP)
• Dietary (pollutants)
• Genetic predisposition (mutations in ⍺-synuclein, LRRK2, GBA)
• Brain trauma, stroke, viral inflammation
• Oxidative stress destroys mitochondria → apoptosis (cell death) of dopaminergic cells.
Pathophysiology
Characteristic features:
1. Loss of dopaminergic neurons in the pars compacta of the substantia nigra
1
,NO general macroscopic atrophy of the brain, but degeneration in certain types of neurons within
particular brain regions.
E.g. early-stage PD: loss of dopaminergic neurons restricted to VL substantia nigra
end-stage PD: more widespread loss
➔ resulting in a reduction of the neurotransmitter dopamine in the basal ganglia
Panels A and B represent the human
postmortem bilateral midbrain of normal
and Parkinsonian subjects, respectively
2. Widespread protein (⍺-synuclein) accumulation (“Lewy Bodies”) in neurons
The basal ganglia
Anatomy
5 interconnected sub-cortical nuclei:
I. Nucleus Caudatus
II. Putamen
III. Globus Pallidus
IV. Nucleus Subthalamicus
V. Substantia Nigra
Function
• Motor control
• Cognitive processes
• Emotional/behavioral processes
➔ Control of global-directed and habitual actions
Basal ganglia disorders are manifested by abnormal movement and a number of neuropsychiatric
disorders
2
,Connectivity
Input Nuclei of the BG:
• Nucleus Caudatus
• Putamen
• Subthalamic Nucleus
Output Nuclei of the BG:
• Globus Pallidus (pars interna)
• Substantia Nigra (pars reticulata)
Cortico-Basal-Ganglia-Thalamo-Cortical Loop = CBGTC Loop
Connections with other cerebral structures
The frontostriatal network
Evolutionary interpretation
Organisms are in need of two systems for circuits
behavioral control:
1. Routine responses to known
environmental stimuli: pre-
programmed behavior, stimulus-
based, procedural, automatic, fast
(walking, shaving, typing)
➔ BASAL GANGLIA
2. Reflective, problem-solving behavior in
new situations, more attention
needed
➔ FRONTAL CORTEX
These two systems are integrated in the FRONTOSTRIATAL NETWORK= involved in motor
cognitive func: thinking,….
3
, Direct Pathway
Netto excitation effect on cortex
Indirect pathway
Netto: inhibitory effect on cortex: keeps indirect movements
from appearing.
Imbalance in neuronal circuits in PD
DIRECT PATHWAY (netto = excitation of cortex)
cortex – striatum – globus pallidus pars interna – thalamus - cortex
INDIRECT PATHWAY (netto = inhibition of cortex)
cortex – striatum – globus pallidus pars externa – nucleus subthalamicus – globus pallidus pars
interna – thalamus – cortex
PD: Dopamine depletion causes imbalance between direct (excitatory) and indirect (inhibitory)
pathways
➔ thalamus is inhibited
➔ movement disorders
4
Theoretical background
Chronic Progressive Degenerative Brain Disorder
Fastest growing neurological disorder
Second-most common neurodegenerative disorder
▪ 2-3% of population ≥65 years of age
Cause: degeneration of dopamine-producing cells in the
substantia nigra of the basal ganglia
Effect: typical motor symptoms, non-motor features and neurobehavioral abnormalities
Epidemiology
Estimated global incidence: 5 to 230 new cases per 100,000 individuals yearly.
Rare before age 50
Incidence 5 to 10-fold from ages 60-90
Global prevalence estimated 0.3%
▪ Increases to >3% in >80 years
Usually: onset between ages 60-70
Genetic variant: Young Onset PD
▪ 5-20% of persons w/ PD
Male:Female distribution ± 1.5:1
Most cases: idiopathic (no known cause)
Most likely a combination of factors:
• Age
• Environmental (toxins, pesiticides, insecticides: rotenone, paraquat, MPTP)
• Dietary (pollutants)
• Genetic predisposition (mutations in ⍺-synuclein, LRRK2, GBA)
• Brain trauma, stroke, viral inflammation
• Oxidative stress destroys mitochondria → apoptosis (cell death) of dopaminergic cells.
Pathophysiology
Characteristic features:
1. Loss of dopaminergic neurons in the pars compacta of the substantia nigra
1
,NO general macroscopic atrophy of the brain, but degeneration in certain types of neurons within
particular brain regions.
E.g. early-stage PD: loss of dopaminergic neurons restricted to VL substantia nigra
end-stage PD: more widespread loss
➔ resulting in a reduction of the neurotransmitter dopamine in the basal ganglia
Panels A and B represent the human
postmortem bilateral midbrain of normal
and Parkinsonian subjects, respectively
2. Widespread protein (⍺-synuclein) accumulation (“Lewy Bodies”) in neurons
The basal ganglia
Anatomy
5 interconnected sub-cortical nuclei:
I. Nucleus Caudatus
II. Putamen
III. Globus Pallidus
IV. Nucleus Subthalamicus
V. Substantia Nigra
Function
• Motor control
• Cognitive processes
• Emotional/behavioral processes
➔ Control of global-directed and habitual actions
Basal ganglia disorders are manifested by abnormal movement and a number of neuropsychiatric
disorders
2
,Connectivity
Input Nuclei of the BG:
• Nucleus Caudatus
• Putamen
• Subthalamic Nucleus
Output Nuclei of the BG:
• Globus Pallidus (pars interna)
• Substantia Nigra (pars reticulata)
Cortico-Basal-Ganglia-Thalamo-Cortical Loop = CBGTC Loop
Connections with other cerebral structures
The frontostriatal network
Evolutionary interpretation
Organisms are in need of two systems for circuits
behavioral control:
1. Routine responses to known
environmental stimuli: pre-
programmed behavior, stimulus-
based, procedural, automatic, fast
(walking, shaving, typing)
➔ BASAL GANGLIA
2. Reflective, problem-solving behavior in
new situations, more attention
needed
➔ FRONTAL CORTEX
These two systems are integrated in the FRONTOSTRIATAL NETWORK= involved in motor
cognitive func: thinking,….
3
, Direct Pathway
Netto excitation effect on cortex
Indirect pathway
Netto: inhibitory effect on cortex: keeps indirect movements
from appearing.
Imbalance in neuronal circuits in PD
DIRECT PATHWAY (netto = excitation of cortex)
cortex – striatum – globus pallidus pars interna – thalamus - cortex
INDIRECT PATHWAY (netto = inhibition of cortex)
cortex – striatum – globus pallidus pars externa – nucleus subthalamicus – globus pallidus pars
interna – thalamus – cortex
PD: Dopamine depletion causes imbalance between direct (excitatory) and indirect (inhibitory)
pathways
➔ thalamus is inhibited
➔ movement disorders
4
