Parkinson's disease
Parkinson's disease, or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor and non-motor systems. The motor symptoms, collectively called parkinsonism, include tremors, slowness in initiating movement, rigidity, and difficulty maintaining balance. Non-motor symptoms such as autonomic nervous system failures, sleep abnormalities, decreased ability to smell, and behavioral changes or neuropsychiatric problems, such as cognitive impairment, psychosis, and anxiety, may appear at any stage of the disease. Symptoms typically develop gradually and non-motor issues become more prevalent as the disease progresses.
Parkinson's disease has no single cause: rather, genetic and environmental factors interact to affect critical cellular processes.
Parkinson's disease involves the gradual decay and loss of dopamine producing neurons in a brain region called the substantia nigra and other related cell groups in the brainstem. This is accompanied by the accumulation of misfolded proteins such as alpha-synuclein which can build up to form clumps of proteins called Lewy bodies if not cleared from cells by cellular degradation systems. Accumulation stimulates the release of pro-inflammatory molecules by the microglia, a protective response that can cause neuroinflammation and neuronal damage, and disrupt metabolic systems if it becomes chronic.
Diagnosis is primarily based on signs and symptoms, typically motor-related, identified through neurological examination. Medical imaging techniques such as PET scanning can support the diagnosis. PD typically manifests in individuals over 60, with about one percent affected. In those younger than 50, it is termed "early-onset PD".
No cure for PD is known, and treatment focuses on alleviating symptoms. Initial treatment typically includes levodopa, MAO-B inhibitors, or dopamine agonists. As the disease progresses, these medications become less effective and may cause involuntary muscle movements. Diet and rehabilitation therapies can help improve symptoms. Deep brain stimulation is used to manage severe motor symptoms when drugs are ineffective. Little evidence exists for treatments addressing non-motor symptoms, such as sleep disturbances and mood instability. Life expectancy for those with PD is near-normal, but is decreased for early-onset.
Classification and terminology
Parkinson's disease is a neurodegenerative disease affecting both the central and peripheral nervous systems, characterized by the loss of dopamine-producing neurons in the substantia nigra region of the brain. It is classified as a synucleinopathy due to the abnormal accumulation of the protein alpha-synuclein, which aggregates into Lewy bodies within affected neurons.The loss of dopamine-producing neurons in the substantia nigra causes movement abnormalities, leading to the categorization of Parkinson's as a movement disorder. In 30% of those with PD, disease progression leads to cognitive decline, resulting in Parkinson's disease dementia. Alongside dementia with Lewy bodies, PDD is one of the two subtypes of Lewy body dementia.
The four cardinal motor symptoms of Parkinson's—slowed movements, postural instability, rigidity, and tremor—are called parkinsonism. Parkinsonism is not exclusive to Parkinson's disease and can occur in other conditions, including HIV infection and recreational drug use. Neurodegenerative diseases that feature parkinsonism, but have distinct differences are grouped under the umbrella of Parkinson-plus syndromes, or alternatively, atypical parkinsonian disorders.
Signs and symptoms
Motor
The cardinal motor features are tremor, bradykinesia, rigidity, and postural instability, collectively termed parkinsonism. Appearing in 70–75% of those with PD, tremor is often the predominant motor symptom. Resting tremor is the most common, but kinetic tremors—occurring during voluntary movements—and postural tremor—preventing upright, stable posture—also occur. Tremor largely affects the hands and feet: a classic parkinsonian tremor is "pill-rolling", a resting tremor in which the thumb and index finger make contact in a circular motion at 4–6 Hz frequency.Bradykinesia describes difficulties in motor planning, beginning, and executing, resulting in overall slowed movement with reduced amplitude that affects sequential and simultaneous tasks. Bradykinesia can also lead to hypomimia, reduced facial expressions. Rigidity, also called rigor, refers to a feeling of stiffness and resistance to passive stretching of muscles. Postural instability typically appears in later stages, leading to impaired balance and falls. Postural instability also leads to a forward stooping posture.
Beyond the cardinal four, other motor deficits, termed secondary motor symptoms, commonly occur. Notably, gait disturbances result in the parkinsonian gait, which includes shuffling and paroxysmal deficits, where a normal gait is interrupted by rapid footsteps—known as festination—or sudden stops, impairing balance and causing falls. Most people with PD experience speech problems, including stuttering, hypophonic, "soft" speech, slurring, and festinating speech. Handwriting is commonly altered in PD, decreasing in size—known as micrographia—and becoming jagged and sharply fluctuating. Grip and dexterity are also impaired.
Neuropsychiatric and cognitive
symptoms such as anxiety, apathy, depression, hallucination, and impulse control disorders occur in up to 60% of those with PD. They often precede motor symptoms, vary with disease progression, and may appear at any stage of the disease including the prodromal phase. Fluctuating symptoms including dysphoria, fatigue, and slowness of thought, are also common. Some neuropsychiatric symptoms are not directly caused by neurodegeneration, but rather by its pharmacological management.| Symptom | - |
| Symptom | Prevalence |
| Anxiety | 40–50 |
| Apathy | 40 |
| Depression | 20–40 |
| Impulse control disorders | 36–60 |
| Psychosis |
Cognitive impairments rank among the most prevalent and debilitating non-motor symptoms. These deficits may emerge in the early stages or before diagnosis, and their prevalence and severity tend to increase with disease progression. Ranging from mild cognitive impairment to severe Parkinson's disease dementia, these impairments include executive dysfunction, slowed cognitive processing speed, and disruptions in time perception and estimation.
Autonomic
failures, known as dysautonomia, can appear at any stage of PD. They are among the most debilitating symptoms and greatly reduce quality of life. Although almost all individuals with PD have cardiovascular autonomic dysfunction, only some are symptomatic. Chiefly, orthostatic hypotension—a sustained blood pressure drop of at least 20 mmHg systolic or 10 mmHg diastolic after standing—occurs in 30–50% of cases. This can result in lightheadedness or fainting; subsequent falls are associated with higher morbidity and mortality.Other autonomic failures include gastrointestinal issues such as chronic constipation, impaired stomach emptying and subsequent nausea, excessive salivation, and dysphagia ; all greatly reduce quality of life. Dysphagia, for instance, can prevent pill swallowing and lead to aspiration pneumonia. Urinary incontinence, sexual dysfunction, and thermoregulatory dysfunction—including heat and cold intolerance and excessive sweating—also frequently occur.
Other
Sensory deficits appear in up to 90% of people with PD and are usually present at early stages. Nociceptive and neuropathic pain are common, with peripheral neuropathy affecting up to 55% of individuals. Visual impairments are also frequently observed, including deficits in visual acuity, color vision, eye coordination, and visual hallucinations. An impaired sense of smell is also prevalent. Individuals often struggle with spatial awareness, recognizing faces and emotions, and may experience challenges with reading and double vision.Sleep disorders are highly prevalent in PD, affecting up to 98%. These disorders include insomnia, excessive daytime sleepiness, restless legs syndrome, REM sleep behavior disorder, and sleep-disordered breathing, many of which can be worsened by medication. RBD may begin years before the initial motor symptoms. Individual presentation of symptoms varies, although most people affected by PD show an altered circadian rhythm at some point of disease progression.
PD is also associated with a variety of skin disorders that include melanoma, seborrheic dermatitis, bullous pemphigoid, and rosacea. Seborrheic dermatitis is recognized as a premotor feature that indicates dysautonomia and demonstrates that PD can be detected not only by changes of nervous tissue, but also tissue abnormalities outside the nervous system.
Causes
Parkinson's disease has no single cause: rather, genetic and environmental factors interact and affect critical cellular processes in a complex interplay.Parkinson's disease involves the gradual degeneration of dopamine producing neurons in a brain region called the substantia nigra and other related cell groups in the brainstem. This is accompanied by the accumulation of misfolded proteins such as alpha-synuclein. Alpha-synuclein is normally found in the presynaptic terminals of neurons. If alpha-synuclein is mis-folded and not cleared from cells by cellular degradation systems, it can build up to form clumps of proteins called Lewy bodies and Lewy neurites. Accumulation stimulates the release of pro-inflammatory molecules by the microglia, a protective response that can cause inflammation and neuronal damage if it becomes chronic. Neuroinflammation causes the blood-brain barrier to become more permeable, allowing dangerous substances and inflammatory cells to enter the brain and interfere with metabolic functions. Dysfunction in mitochondria, which are central to cellular energy production, increases oxidative stress and cell death. Protein aggregation, inflammation and metabolic dysregulation in lysosomal, endosomal, and mitochondrial systems are interconnected mechanisms which create a cycle of inflammation, cellular stress and damage in Parkinson's disease.
The cumulative effects of many different environmental exposures over a lifetime interact with underlying genetic factors to influence PD development and progression.
Genetically, about 5–10% of cases are familial while others are classed as idiopathic with no clearly identifiable cause. Variations in specific genes have been identified as risk factors and linked to contributing neural mechanisms. Environmentally, exposures to pesticides, metals, solvents, other toxicants and air pollution are increasingly seen as major risk factors in PD development. The brain is particularly vulnerable to chemicals that are able to cross the blood-brain barrier. Body-first and brain-first models of Parkinson's disease have been proposed to explain the connection of PD mechanisms with exposure to known environmental risk factors via the gut and the olfactory system. Traumatic brain injury and Type 2 diabetes are additional risk factors.
Exercise, coffee consumption, and diets rich in fruits, vegetables, whole grains, and fish are protective factors associated with lower risk of PD.