11.1 Introduction to Parkinson’s Disease
4 min read•june 18, 2024
is a complex neurological disorder affecting movement and cognition. It's caused by the loss of -producing brain cells, leading to symptoms like tremors, stiffness, and slow movement. Understanding its mechanisms is crucial for developing effective treatments.
Diagnosis involves clinical assessment, brain scans, and response to medication. While there's no cure, treatments can manage symptoms and improve quality of life. Ongoing research aims to uncover the root causes and develop new therapies for this challenging condition.
Pathophysiology and Clinical Presentation of Parkinson's Disease
Mechanisms of Parkinson's disease
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- Degeneration of dopaminergic neurons in the pars compacta (SNpc)
- Leads to decreased dopamine levels in the (caudate nucleus and putamen)
- Disrupts the balance of the circuitry, affecting motor control and movement initiation
- Accumulation of abnormal protein aggregates called
- Primarily composed of misfolded protein, which contributes to neuronal dysfunction and cell death
- Found in surviving neurons of the SNpc and other brain regions (cortex, amygdala, locus coeruleus)
- Impairment of the
- Affects the initiation and control of voluntary movements, resulting in motor symptoms (, , )
- Caused by the loss of dopaminergic neurons projecting from the SNpc to the striatum
- Neurotransmitter imbalances
- Reduced dopamine levels lead to increased activity of the indirect pathway (inhibitory), resulting in excessive inhibition of the thalamus and
- Decreased activity of the direct pathway (excitatory), further contributing to the motor symptoms of Parkinson's disease
- Imbalance between dopamine and other (, , ) in the basal ganglia
Symptoms of Parkinson's disease
- Motor symptoms
- Bradykinesia: slowness of movement, difficulty initiating and executing tasks (buttoning shirts, tying shoelaces)
- Rigidity: stiffness of muscles, resistance to passive movement, often described as "lead-pipe" or "cogwheel" rigidity
- Resting tremor: typically unilateral, 4-6 Hz frequency, most prominent in the hands ("pill-rolling" tremor) and less common in the legs or jaw
- : impaired balance and coordination, increased risk of falls, especially in later stages of the disease
- Gait disturbances: shuffling gait, reduced arm swing, difficulty turning, and freezing of gait (sudden, brief inability to move)
- Non-motor symptoms
- Cognitive impairment and dementia: difficulty with attention, executive function, and memory, increased risk of developing dementia in advanced stages
- Depression and anxiety: common mood disorders that can precede motor symptoms and affect quality of life
- Sleep disorders: (acting out dreams), insomnia, excessive daytime sleepiness
- Autonomic dysfunction: (drop in blood pressure upon standing), constipation, urinary frequency or urgency
- Olfactory dysfunction: reduced sense of smell (), often an early non-motor symptom
- Physical signs
- Masked facial expression (): reduced facial muscle movement, leading to a "poker face" appearance
- : small, cramped handwriting that becomes progressively smaller and more difficult to read
- Soft and monotonous speech (): reduced volume and lack of inflection in speech
- Drooling (): due to reduced swallowing frequency and impaired control of oral and pharyngeal muscles
- Stooped posture and festinating gait: flexed posture and short, shuffling steps with a tendency to accelerate while walking
Causes and diagnosis of Parkinson's
- Potential causes
- Genetic factors
- Familial Parkinson's disease: accounts for 5-10% of cases, with mutations in genes (, , , , )
- Genetic susceptibility: certain genetic variations increase the risk of developing Parkinson's disease
- Environmental factors
- Exposure to pesticides, herbicides, and heavy metals (rotenone, paraquat, manganese)
- Rural living and well-water consumption, possibly due to increased exposure to environmental toxins
- Aging
- Increased risk with advancing age, with an average age of onset around 60 years
- Age-related changes in the brain may contribute to the development of Parkinson's disease
- Genetic factors
- Diagnostic methods
- Clinical assessment
- Detailed medical history and neurological examination to assess motor symptoms and exclude other conditions
- Assessment of motor symptoms using the (UPDRS), which evaluates speech, facial expression, tremor, rigidity, bradykinesia, and postural stability
- Neuroimaging techniques
- Dopamine transporter (DaT) scan using single-photon emission computed tomography (SPECT): assesses the integrity of dopaminergic neurons in the striatum, helping to differentiate Parkinson's disease from essential tremor and drug-induced parkinsonism
- Magnetic resonance imaging (MRI) and computed tomography (CT): rule out other causes of parkinsonism (vascular parkinsonism, multiple system , normal pressure hydrocephalus)
- test
- Administering levodopa, a dopamine precursor, to observe the patient's response
- Significant improvement in motor symptoms (>30% reduction in UPDRS score) supports the diagnosis of Parkinson's disease
- Exclusion of other causes of parkinsonism
- Essential tremor: typically involves action tremor rather than resting tremor and does not respond to levodopa
- Drug-induced parkinsonism: caused by dopamine-blocking medications (antipsychotics, antiemetics) and resolves upon discontinuation of the offending drug
- Progressive supranuclear palsy: characterized by early postural instability, supranuclear gaze palsy, and poor response to levodopa
- Corticobasal degeneration: presents with asymmetric apraxia, cortical sensory loss, and alien limb phenomenon, in addition to parkinsonism
- Clinical assessment
Historical and Cellular Aspects of Parkinson's Disease
- First described by in 1817 in his "Essay on the Shaking Palsy"
- in Parkinson's disease primarily affects dopaminergic neurons in the substantia nigra
- contributes to the progressive loss of dopaminergic neurons
- plays a role in the pathogenesis of Parkinson's disease
- Impaired function of the motor cortex results from the loss of dopaminergic input
Key Terms to Review (48)
Acetylcholine: Acetylcholine is a neurotransmitter that plays a crucial role in the functioning of the nervous system, including the transmission of signals between nerve cells and the activation of muscle contractions. It is a key component in understanding various neurological disorders and the mechanisms of drugs used to treat them.
Akathisia: Akathisia is a movement disorder characterized by an inner feeling of restlessness and an urgent need to move. It is often a side effect of antipsychotic and other psychopharmacologic drugs.
Alpha-synuclein: Alpha-synuclein is a protein found primarily in neural tissue, implicated in the pathogenesis of Parkinson's disease. It aggregates to form Lewy bodies, which are a hallmark of the disease.
Atrophy: Atrophy is the gradual decline or shrinkage of muscle or tissue due to underuse, disease, or lack of neurological stimulation. It is a common feature in chronic conditions like Parkinson's Disease and Multiple Sclerosis.
Basal Ganglia: The basal ganglia are a group of subcortical nuclei in the brain that play a crucial role in the control and regulation of voluntary movement, as well as other important functions such as procedural learning, habit formation, and certain aspects of emotion and cognition. This term is particularly relevant in the context of understanding Parkinson's disease and the development of anti-Parkinsonian drugs.
Bradykinesia: Bradykinesia is a key symptom of Parkinson's disease, characterized by slowness of movement and difficulty initiating voluntary movements. It is a central feature of the motor impairments associated with this neurodegenerative disorder and a primary target for anti-Parkinsonian drug therapies.
Carbidopa/levodopa extended release: Carbidopa/levodopa extended release is a combination medication used to treat symptoms of Parkinson’s disease by replenishing dopamine. The extended-release formulation allows for a more consistent delivery of the medication over time.
DaT Scan: A DaT scan, also known as a dopamine transporter (DAT) scan, is a type of nuclear imaging test that measures the levels of dopamine transporters in the brain. It is primarily used in the diagnosis and evaluation of Parkinson's disease and other movement disorders.
DJ-1: DJ-1 is a protein that plays a crucial role in the pathogenesis of Parkinson's disease. It is a multifunctional protein that acts as a sensor for oxidative stress and is involved in various cellular processes, including transcriptional regulation, mitochondrial function, and protection against oxidative damage.
Dopamine: Dopamine is a neurotransmitter that plays a crucial role in the brain's reward and pleasure centers, as well as in the regulation of various physiological processes. It is involved in a wide range of functions, from motor control and cognition to emotional and behavioral responses, making it a key player in understanding and treating numerous nervous system disorders.
Dystonia: Dystonia is a movement disorder characterized by involuntary muscle contractions causing repetitive movements or abnormal postures. It can be a symptom of various neurological conditions, including Parkinson's Disease.
GABA: GABA (Gamma-Aminobutyric Acid) is the primary inhibitory neurotransmitter in the central nervous system. It plays a crucial role in regulating neuronal excitability and has been associated with various neurological and psychiatric disorders, including Parkinson's disease, epilepsy, mood disorders, and alcohol use disorder.
GABA structural analogs: GABA structural analogs are compounds that mimic the structure of gamma-aminobutyric acid (GABA), a neurotransmitter. These analogs are used to modulate neural activity and are often employed in the treatment of neurological conditions such as multiple sclerosis.
Geographic regions: Geographic regions are areas of land that are divided by natural or artificial boundaries and have distinct characteristics. In pharmacology, these regions can impact the prevalence and treatment efficacy of diseases.
Glutamate: Glutamate is the principal excitatory neurotransmitter in the mammalian central nervous system, playing a crucial role in various neurological processes and disorders affecting the brain and nervous system.
Hypomimia: Hypomimia is a reduced or diminished facial expression, a common symptom observed in individuals with Parkinson's disease. It is characterized by a masked, immobile, or limited facial movement, resulting in a lack of emotional expressiveness.
Hypophonia: Hypophonia is a speech disorder characterized by a soft, low-volume voice that is difficult to hear or understand. It is a common symptom associated with Parkinson's disease, a neurodegenerative disorder affecting movement and speech.
Hyposmia: Hyposmia is a reduced ability to detect or identify odors, often experienced as a partial or diminished sense of smell. This condition can have various underlying causes and is commonly associated with certain neurological disorders, such as Parkinson's disease, as well as upper respiratory system conditions.
James Parkinson: James Parkinson was an English surgeon, apothecary, and paleontologist who is best known for his 1817 essay that first described the condition now known as Parkinson's disease. His groundbreaking work laid the foundation for the understanding and treatment of this neurological disorder.
Levodopa: Levodopa is a medication used to treat the symptoms of Parkinson's disease, a neurodegenerative disorder characterized by motor impairments. It is the primary and most effective pharmacological treatment for managing the motor symptoms associated with Parkinson's disease.
Lewy Bodies: Lewy bodies are abnormal protein deposits that develop inside the nerve cells of individuals with Parkinson's disease. They are the hallmark pathological feature of this neurodegenerative disorder and are associated with the progressive loss of dopamine-producing neurons in the brain.
LRRK2: LRRK2 (Leucine-Rich Repeat Kinase 2) is a gene that encodes a large, multi-domain protein known as LRRK2. This protein is a key player in the pathogenesis of Parkinson's disease, as mutations in the LRRK2 gene are the most common known genetic cause of this neurodegenerative disorder.
The LRRK2 protein is involved in various cellular processes, including vesicle trafficking, cytoskeletal dynamics, and mitochondrial function, all of which are important for the health and survival of dopaminergic neurons in the brain.
Males: Males are biological individuals with XY chromosomes, typically presenting male reproductive organs and secondary sexual characteristics. In medical contexts, males may exhibit different responses to certain diseases and treatments compared to females due to hormonal and genetic differences.
Micrographia: Micrographia is a condition characterized by abnormally small and cramped handwriting, often seen in patients with Parkinson's disease. It results from motor deficits associated with the illness.
Micrographia: Micrographia is a neurological symptom characterized by abnormally small and cramped handwriting, often associated with Parkinson's disease. It is a result of the motor impairments and bradykinesia (slowness of movement) that are hallmarks of Parkinson's disease.
Mitochondrial Dysfunction: Mitochondrial dysfunction refers to the impairment or abnormal functioning of the mitochondria, the powerhouses of cells responsible for generating energy through cellular respiration. This disruption in mitochondrial activity can lead to various metabolic and neurological disorders, including Parkinson's disease.
Motor Cortex: The motor cortex is the region of the cerebral cortex responsible for initiating and controlling voluntary movement. It is a critical component in the neural pathways that regulate and coordinate motor functions throughout the body.
Neurodegeneration: Neurodegeneration is the progressive loss of structure or function of neurons, including the death of neurons. It is a key feature in the pathogenesis of various neurodegenerative diseases, such as Alzheimer's, Parkinson's, and multiple sclerosis.
Neurotransmitters: Neurotransmitters are chemical messengers that transmit signals between neurons and target cells in the nervous system. They are responsible for the communication and coordination of various physiological and psychological processes in the body, and their imbalance or dysfunction can contribute to the development of various neurological and psychiatric disorders.
Nigrostriatal Pathway: The nigrostriatal pathway is a crucial neural circuit in the brain that plays a central role in the development and progression of Parkinson's disease. It is a dopaminergic pathway that connects the substantia nigra, a region in the midbrain, to the striatum, a key component of the basal ganglia involved in motor control and coordination.
Orthostatic Hypotension: Orthostatic hypotension is a sudden drop in blood pressure that occurs when an individual stands up from a sitting or lying position. This condition can lead to dizziness, lightheadedness, and even fainting, and is particularly relevant in the context of various medical conditions and drug therapies.
Oxidative Stress: Oxidative stress is an imbalance between the production of free radicals and the body's ability to counteract their harmful effects through antioxidant defenses. It is a key contributor to the pathogenesis of various neurodegenerative diseases, including Alzheimer's and Parkinson's.
Parkinson's Disease: Parkinson's disease is a chronic and progressive neurological disorder that primarily affects the motor system. It is characterized by the loss of dopamine-producing neurons in the brain, leading to a variety of symptoms that can significantly impact an individual's quality of life. This term is particularly relevant in the context of understanding the characteristics of drugs used to treat nervous system disorders, as well as the specific anti-parkinsonian drugs that are designed to manage the symptoms of this condition.
Parkinson’s disease (PD): Parkinson’s disease (PD) is a chronic, progressive neurological disorder characterized by the degeneration of dopamine-producing neurons in the brain. This leads to motor symptoms such as tremors, rigidity, and bradykinesia.
PINK1: PINK1 (PTEN-induced putative kinase 1) is a gene that encodes a protein kinase involved in the regulation of mitochondrial function and quality control. It plays a crucial role in the pathogenesis of Parkinson's disease, a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the brain.
Postural Instability: Postural instability refers to the impaired ability to maintain proper body posture and balance, a common symptom associated with Parkinson's disease. It involves difficulties in controlling and coordinating the movements required to keep the body upright and stable, leading to an increased risk of falls and impaired mobility.
PRKN: PRKN, also known as the Parkin gene, is a crucial gene associated with the development and progression of Parkinson's disease. It encodes the Parkin protein, which plays a vital role in the regulation of mitochondrial function and the removal of damaged mitochondria through a process called mitophagy.
REM Sleep Behavior Disorder: REM sleep behavior disorder (RBD) is a parasomnia characterized by the loss of normal muscle atonia during rapid eye movement (REM) sleep, leading to abnormal, often violent, motor behaviors that correspond to the content of the individual's dream. This condition is closely associated with the development of neurodegenerative disorders, particularly Parkinson's disease.
Rigidity: Rigidity refers to the increased muscle tone and resistance to passive movement observed in individuals with Parkinson's disease. It is a cardinal motor symptom of the disease and is closely associated with the anti-parkinsonian drugs used to manage the condition.
Rust Belt: The Rust Belt is a region in the United States characterized by industrial decline, aging factories, and decreasing population. It spans parts of the Midwest and Northeast, historically known for manufacturing and steel production.
Sialorrhea: Sialorrhea, also known as drooling or hypersalivation, is the unintentional and excessive flow of saliva from the mouth. It is a common symptom associated with various neurological and medical conditions, particularly Parkinson's disease.
SNCA: SNCA, also known as alpha-synuclein, is a small protein that is primarily found in the presynaptic terminals of neurons. It is a key player in the pathogenesis of Parkinson's disease and other neurodegenerative disorders known as synucleinopathies.
Striatum: The striatum is a group of structures located deep within the cerebral hemispheres of the brain. It is a crucial component of the basal ganglia, a network of interconnected brain regions responsible for various motor functions, learning, and habit formation.
Substantia Nigra: The substantia nigra is a midbrain structure that plays a crucial role in the pathogenesis of Parkinson's disease and the mechanism of action of anti-Parkinsonian drugs. It is a collection of dopaminergic neurons that are responsible for producing the neurotransmitter dopamine, which is essential for motor control and coordination.
Tardive dyskinesia: Tardive dyskinesia is a neurological disorder characterized by involuntary, repetitive body movements. It is often caused by long-term use of antipsychotic medications.
Tremor: A tremor is an involuntary, rhythmic shaking movement of a body part, often the hands, head, or voice. Tremors can be a symptom of various neurological and medical conditions, and they can also occur as a side effect of certain medications.
Unified Parkinson's Disease Rating Scale: The Unified Parkinson's Disease Rating Scale (UPDRS) is a comprehensive assessment tool used to evaluate the severity of Parkinson's disease. It provides a standardized way to measure the motor and non-motor symptoms associated with this neurodegenerative disorder, allowing healthcare professionals to track the progression of the disease and the effectiveness of treatments.
α-synuclein: α-synuclein is a small, naturally occurring protein found primarily in the presynaptic terminals of neurons. It is a key player in the pathogenesis of Parkinson's disease and other neurodegenerative disorders known as synucleinopathies, where abnormal aggregation and accumulation of this protein is a hallmark feature.