Parkinson's disease

Parkinson’s disease, also referred to as Parkinson disease, Parkinson’s, or PD, is a movement disorder characterized by the degeneration of dopamine-producing neurons in the brain’s substantia nigra.

It is among the most prevalent neurological disorders, typically manifesting in adulthood and increasing in incidence with age. Often, the cause of Parkinson’s remains unknown, although genetic factors, such as mutations in the PINK1, parkin, or alpha-synuclein genes, can contribute in some cases. In rare instances, Parkinsonian symptoms might be triggered by MPTP, a harmful byproduct found in the recreational drug MPPP or desmethylprodine, a synthetic opioid.

Additionally, several risk factors might collectively predispose individuals to Parkinson’s, such as exposure to pesticides or genetic variations in genes like LRRK2.

Regardless of the specific cause, the disorder originates from the loss of dopaminergic neurons in the substantia nigra, which appears darker than surrounding brain areas in autopsy slices—hence its name, meaning "black substance."

Typically, the substantia nigra is referenced as a singular area, but it actually comprises two segments situated on either side of the midbrain, forming part of the basal ganglia. These structures regulate movement via their interactions with the motor cortex.

In Parkinson’s, the dark regions of the substantia nigra progressively fade. Microscopically, Lewy bodies—eosinophilic, round inclusions consisting of alpha-synuclein protein—accumulate in the neurons of this area before their demise. The functions of alpha-synuclein and the significance of Lewy bodies, which are also observed in other conditions like Lewy body dementia and multiple system atrophy, remain unclear.

The substantia nigra divides into two subregions. The pars reticulata receives and transmits signals from the striatum (comprising the caudate and putamen) to the thalamus via GABA-rich neurons. The pars compacta, primarily affected in Parkinson’s, sends dopamine-rich signals to the striatum, creating the nigrostriatal pathway crucial for initiating movement. Consequently, the death of neurons in the pars compacta leads to a hypokinetic state typical of Parkinson’s.

Beyond initiating movements, the substantia nigra also refines movement execution, contributing to Parkinson’s characteristic symptoms.

The most recognizable symptom is the tremor, a “pill-rolling” type seen as a shaking motion in the hands, particularly when at rest, which decreases with movement.

Rigidity, another symptom, is a stiffness that can manifest as “cogwheel” rigidity—periodic resistance felt when moving a person's limbs. This rigidity also contributes to the stooped posture and diminished facial expressions observed in many patients with Parkinson’s.

Bradykinesia, hypokinesia, and akinesia are conditions characterized by slow, reduced, and absent movements, respectively, all arising from challenges in initiating movement in Parkinson's disease. Symptoms include legs freezing mid-step and a shuffling gait with small steps.

A later symptom of the disease, postural instability, leads to balance issues and increases the risk of falls.

Unlike some neurological disorders, Parkinson’s does not cause muscle weakness, which distinguishes it from diseases impacting the motor cortex or corticospinal pathway. Furthermore, the characteristic resting tremor of Parkinson’s helps to differentiate it from cerebellar diseases, which often involve an action or intention tremor—where the tremor intensifies during movement. The presence of bradykinesia and postural instability also helps to distinguish Parkinson’s from essential tremor, which typically features an action tremor.

Parkinson's can also affect non-motor brain functions, leading to depression, dementia, sleep disturbances, and olfactory deficits. These symptoms may stem from disrupted dopaminergic signaling in areas beyond the substantia nigra, such as the prefrontal cortex, which affects cognitive functions, or from imbalances in other neurotransmitters like acetylcholine.

Though there is no cure for the progressive neurodegeneration in Parkinson’s, treatments are available to manage symptoms. The primary treatment approach is to enhance dopamine signaling in the brain. Dopamine cannot cross the blood-brain barrier, but its precursor, levodopa, can. Once inside the brain, levodopa is converted to dopamine primarily within the remaining nigrostriatal neurons. Peripheral metabolism of levodopa into dopamine and other catecholamines can cause side effects like arrhythmias, hence the co-administration of levodopa with carbidopa, an inhibitor of dopa decarboxylase that does not cross the blood-brain barrier.

Other therapeutic approaches include amantadine, which boosts endogenous dopamine production through mechanisms still being elucidated, and dopamine agonists like bromocriptine, pramipexole, and ropinirole, which mimic dopamine’s effects and stimulate dopamine receptors.

COMT inhibitors such as entacapone and tolcapone are used alongside levodopa to prevent the breakdown of both dopamine and levodopa outside the central nervous system, enhancing their availability to the brain. Similarly, medications like selegiline inhibit monoamine oxidase B (MAO-B), which metabolizes dopamine.

To counteract the increased acetylcholine signaling resulting from reduced dopamine, anticholinergics like benztropine are administered to balance dopaminergic and cholinergic signaling and improve tremors. Additionally, deep-brain stimulation, involving an implant that sends electrical signals to the basal ganglia, is employed to address abnormal neural signaling in Parkinson's.

The term "parkinsonism" describes Parkinson-like symptoms that occur in other neurological diseases or as side effects of certain medications, such as antipsychotics like haloperidol, which blocks dopamine receptors, and metoclopramide, used to manage vomiting.

In summary, Parkinson’s disease is a progressive movement disorder resulting from the deterioration of dopamine-producing neurons in the substantia nigra, particularly in the pars compacta, leading to characteristic symptoms such as resting tremor, rigidity, and difficulties with movement initiation and balance, with treatments primarily aimed at increasing brain dopamine levels.

Ref:

"Robbins Basic Pathology" Elsevier (2017)

"Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)

"Pathophysiology of Disease: An Introduction to Clinical Medicine 7/E (ENHANCED EBOOK)" McGraw Hill Professional (2014)

"CURRENT Medical Diagnosis and Treatment 2020" McGraw Hill Professional (2019)

"Parkinson's disease" The Lancet (2015)

"Parkinson's disease" The Lancet (2004)

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