From the Guidelines
Parkinson's disease is a neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra/striatum, leading to the formation of Lewy bodies and a significant reduction in dopamine levels, resulting in the hallmark motor symptoms of resting tremor, bradykinesia, and rigidity. The pathophysiology of Parkinson's disease (PD) is complex and involves multiple pathways. According to the most recent evidence [ 1 ], PD is a synucleinopathy with neuronal deposits of Lewy bodies, predominantly composed of alpha-synuclein and ubiquitin. The clinical presentation of PD is related to the progressive degeneration of dopaminergic neurons in the substantia nigra projecting to the striatum.
Key Features of Parkinson's Disease
- Progressive degeneration of dopaminergic neurons in the substantia nigra/striatum
- Formation of Lewy bodies, abnormal protein aggregates primarily composed of misfolded alpha-synuclein protein
- Significant reduction in dopamine levels in the basal ganglia, particularly the striatum
- Imbalance in the direct and indirect pathways of the basal ganglia circuit, resulting in excessive inhibitory output from the globus pallidus interna and substantia nigra pars reticulata to the thalamus
- Cardinal motor symptoms: resting tremor, bradykinesia, rigidity, and postural instability
Non-Motor Symptoms
The disease also affects non-dopaminergic systems, including cholinergic, noradrenergic, and serotonergic pathways, which explains the non-motor symptoms such as:
- Cognitive impairment
- Autonomic dysfunction
- Sleep disorders
- Mood disturbances
Pathogenesis
Both genetic factors (mutations in genes like SNCA, LRRK2, and PARK2) and environmental factors (toxins, head trauma) contribute to the pathogenesis, often through mechanisms involving:
- Mitochondrial dysfunction
- Oxidative stress
- Neuroinflammation
- Impaired protein clearance systems
The estimated interval between initial loss of dopaminergic neurons and the appearance of symptoms is approximately 5 years, after approximately 40% to 50% of the dopaminergic neurons in the substantia nigra have been lost [ 1 ]. Correctly diagnosing a Parkinsonian syndrome on clinical features alone can be quite challenging, and imaging remains an essential diagnostic tool in the evaluation of a patient presenting with Parkinsonian symptoms [ 1 ].
From the Research
Pathophysiology of Parkinson's Disease
The pathophysiology of Parkinson's disease (PD) is a complex process involving the progressive loss of dopamine neurons in the central nervous system, leading to a significant disability due to a combination of motor and non-motor symptoms 2.
Key Features of PD Pathophysiology
- Progressive loss of dopaminergic neurons and decreased dopamine content in the substantia nigra pars compacta 3
- Disturbances of dopamine synthesis, storage, transportation, and metabolism contributing to neurodegeneration of dopaminergic neurons 3
- Dopamine depletion shifting the basal ganglia toward inhibiting cortically generated movements, leading to motor complications 4
- Involvement of dopamine loss in extrastriatal basal ganglia nuclei, including the globus pallidus and subthalamic nucleus, in the pathophysiology of PD 5
Genetic and Environmental Factors
- PD is caused by a combination of environmental factors and genetic variants, ranging from highly penetrant Mendelian alleles to alleles that only modestly increase disease risk 6
- Genetic variants affecting endosomal, lysosomal, and mitochondrial dysfunction in PD pathophysiology, with α-synuclein playing a key role in all three pathways 6