Parkinson's Disease: Etiology, Genetics, and Risk

• Parkinson's disease (PD) is a slowly progressive neurodegenerative disease.
• It is characterized by asymmetrical resting tremor, bradykinesia, rigidity, and postural changes.
• PD is the second most common neurodegenerative disease after Alzheimer's, affecting about 5 million people globally.
• PD prevalence is approximately 0.3% in the general population.
• Prevalence increases from 1% in those over 60 to 4% in those over 80 years old.
• The mean age at diagnosis is 70.5 years, with incidence rising sharply after 65.
• It is uncommon in people under 40.
• There are 50% more men with PD than women, but the disease progresses faster in women.
• The risk of developing PD doubles if a first-degree relative has it.
• PD is now seen as a complex disorder with diverse motor and non-motor features.
• Neuropsychiatric manifestations can occur in addition to motor symptoms.
• The exact causes of neurodegeneration in PD are not fully understood.
• Causes include genetic and environmental factors, protein processing abnormalities, oxidative stress, mitochondrial dysfunction, and inflammation.
• PD is a complex genetic disease with at least 15 different genetic markers.
• Purely genetic forms of Parkinson's likely affect only a small percentage of people.

Risk factors for PD:

• Age
• Family history
• Exposure to herbicides/pesticides
• Head trauma with concussion
• Exposure to heavy metals
• Exposure to hydrocarbon solvents like trichloroethylene
• Milk consumption

Pathophysiology

• PD develops from dopamine depletion in the substantia nigra and nigrostriatal pathway.
• Depigmentation, neuronal loss, and gliosis occur primarily in the substantia nigra pars compacta and locus ceruleus.
• Dopamine depletion leads to increased inhibition of the thalamus and reduced motor cortex input.
• Key features are tremor at rest, rigidity, bradykinesia (or akinesia), and postural instability (TRAP).
• Compensatory mechanisms like acetylcholine-secreting neurons initially mask dopamine depletion effects.

Clinical Presentation and Physical Examination

• Clinical features include asymmetrical tremor, rigidity, bradykinesia with freezing, and flexed posture.
• Subtypes include tremor dominant, akinetic-rigid, and postural instability/gait difficulty.
• Rest tremor occurs when muscles are relaxed, usually unilateral, and disappears with movement.
• "Pill rolling" hand tremor increases with walking.
• Essential tremor improves with walking, differentiating it from PD.
• Most patients exhibit a slow, coarse tremor (2-5 oscillations per second) at rest.
• Rigidity involves increased resistance to passive joint movement in all directions.
• Cogwheeling (ratcheting) may occur during movement.
• Rigidity increases when another limb is engaged in active movement.
• Bradykinesia is the general slowness of motion.
• Akinesia is the lack of voluntary movement.
• Hypokinesia refers to movements that are smaller than they should be, like micrographia.
• Other symptoms involve shuffling gait with decreased arm swing and freezing.
• Some experience festination (rapid, short steps).
• Masked facies (reduced facial expression) and decreased blinking are common.
• Speech becomes soft (hypophonia) and monotonous.
• Some patients experience unclear enunciation (dysarthria) or repetition of syllables (palilalia).
• Levodopa treatment can improve all of these features.
• Patients often have a flexed posture with head bowed, trunk bent forward, and flexed limbs.
• Lateral trunk tilting (Pisa syndrome) is also common.
• Postural reflexes are tested via the pull test.
• Rigidity is tested by flexing and extending the elbow or pronating-supinating the forearm.
• Gait assessment reveals shuffling, short strides, and reduced arm swing.
• Festination can also be observed during gait assessment.
• Turning involves the head, trunk, and pelvis moving as one (turn en block).
• Freezing is a transient inability to perform active movements.
• Patients can overcome freezing by intentionally raising their legs or cycling.
• Kinesia paradoxa is the sudden ability to move normally when physically cued, despite immobility.

Diagnostics

• Diagnosis relies on clinical presentation and physical exam findings.
• Two of the three cardinal signs (tremor, bradykinesia, rigidity) must be present.
• Rest tremor with unilateral onset and positive response to dopaminergic therapy are key indicators.
• Diagnostic studies are not usually indicated.
• Neuroimaging is typically normal.
• DaTscan uses a radioactive tracer to detect dopaminergic neurons.
• Decreased tracer uptake suggests PD, but cannot distinguish PD from PSP or MSA.
• DaTscan can differentiate PD from secondary parkinsonism or essential tremor
• Postmortem neuropathologic examination remains the gold standard for diagnosis.
• It can be difficult to get insurances to cover a DaTscan, referral to a neurologist is indicated.
• Noting midbrain Lewy bodies is especially important.

Differential Diagnosis

• Other neurodegenerative disorders with similar signs include essential tremor, dementia with Lewy bodies, corticobasal degeneration, MSA, and PSP.
• Secondary parkinsonism can result from drug reactions, infections, metabolic disorders, trauma, neoplastic disorders, toxicity, and vascular disorders.
• Diagnosis of PD and other parkinsonism forms relies on response to levodopa.
• Bradykinesia and rigidity respond best, but lack of improvement does not exclude PD.
• Tremor may not always respond to levodopa.
• It is key to rule out other conditions that fit the symptoms if a patient does not respond to levodopa treatment

Alternative Diagnosis Indicators:

• Falls early in the disease
• Poor response to levodopa
• Symmetrical motor signs
• Rapid progression to bilateral mild to moderate disease
• Lack of tremor
• Early dysautonomia (urinary urgency/incontinence, fecal incontinence, erectile failure, orthostatic hypotension)

Interprofessional Collaborative Management

• Treatment aims to alleviate symptoms and maximize function, but does not slow disease progression.
• Treatment is individualized.
• The goal is to maintain independence and functional ability for as long as possible.
• Medical treatment either increases dopaminergic system function or reduces cholinergic influence.
• The decision to start medication is based on functional impairment.

Pharmacologic Management

• Selegiline: A selective monoamine oxidase type B inhibitor with potential neuroprotective properties.

• Might delay nigral neuron destruction and inhibit dopamine breakdown.

• Does not produce functional benefit as monotherapy but may delay need for levodopa.

• Increases dopaminergic effect and can contribute to dopaminergic toxicity when given with levodopa.

• Maximum dose is 5 mg twice daily.

• Levodopa: The most effective drug for symptomatic treatment, especially for akinetic symptoms.

• Restores dopamine in the basal ganglia.

• Dopamine does not cross the blood-brain barrier; levodopa, its precursor, is given instead.

• Levodopa is metabolized peripherally and centrally. Peripheral metabolism leads to side effects.

• Sinemet combines levodopa with carbidopa to block peripheral metabolism.

• Initial treatment is with small doses, titrated to the lowest effective dose.

• Absence of response to 1000-1500 mg/day suggests incorrect diagnosis.

• The optimal carbidopa dose is 100-150 mg/day to block peripheral levodopa metabolism.

• Levodopa carries a higher risk for dyskinesia versus dopamine agonists.

• Immediate-release preparations are used initially to evaluate response.

• Slow-release forms provide longer half-life and lower peak plasma level, reducing fluctuations.

• Reassessments every 3-6 months are necessary when the patient's condition is considered stable

• Dopamine Agonists: Synthetic agents that directly stimulate dopamine receptors and do not require metabolic conversion.

• They are not dependent on neuronal uptake or release.

• Offer a longer duration of action compared to immediate-release levodopa.

• DAs are used for adjunctive treatment of advanced PD with reduced levodopa response, motor fluctuations, dyskinesia, and other adverse effects.

• Some advocate early use of DAs as a levodopa-sparing strategy.

• Given the potential that DAs are associated with fewer motor fluctuations and the evidence of a higher incidence of levodopa-related dyskinesia in young-onset PD, some experts suggest that DAs for initial treatment of young-onset PD (in patients below 60 years of age) is appropriate, whereas the more effective levodopa is used in patients above 60 years of age. Ropinirole (Requip), pramipexole (Mirapex), and bromocriptine (Parlodel) are DAs that can be effective adjuncts to levodopa in older-onset PD patients or as monotherapy in young-onset PD patients.

• Can cause orthostatic hypotension when first introduced.

• Starting regimen: small dose at bedtime for 3 days, then switch to daytime administration with gradual increase.

• Bromocriptine and ropinirole may induce psychosis and confusion; pramipexole induces somnolence.

• Use with caution in patients with cardiac disease.

• DAs require maintenance doses at least 3 times a day.

• Adverse effects include nausea, vomiting, sleepiness, orthostatic hypotension, confusion, and hallucinations.

• Increased risk of impulse control disorders, including pathologic gambling, compulsive sexual behavior, and compulsive buying.

• Catechol O-Methyltransferase Inhibitors: COMT inhibitors, such as entacapone (Comtan), are ineffective if given alone, but they prolong and potentiate the effect of levodopa when they are given in conjunction with levodopa.

• COMT inhibitors are used to treat motor fluctuations in patients experiencing end-of-dose "wearing-off" periods.

• Examples: Tolcapone (Tasmar) and entacapone.

• Anticholinergics: Anticholinergics should be used in younger patients in whom tremor is the predominant issue.

• Dopamine and acetylcholine are normally in a state of electrochemical balance in the basal ganglia.

• In PD, dopamine depletion produces cholinergic sensitivity so that cholinergic drugs exacerbate PD and anticholinergic drugs improve PD symptoms.

• Centrally acting anticholinergic drugs, such as trihexyphenidyl (Artane) and benztropine (Cogentin), are more useful in controlling tremor and rigidity than bradykinesia but can also cause typical side effects.

• The potency of anticholinergics seems to decrease over time, and side effects such as blurred vision, dry mouth, bowel and bladder disorders, and cognition changes limit their usefulness.

• Evidence of benefit of anticholinergics is unclear.

• These drugs should not be used in older adults because of a well-documented risk of mental status change and are contraindicated in patients taking antidementia drugs.

• Amantadine: Is an antiviral agent that has mild antiparkinsonian activity.

• The mechanism of action is uncertain, but it increases dopamine release, inhibits dopamine reuptake, and stimulates dopamine receptors.

• It may even have a central anticholinergic effect.

• Controlled trials demonstrated that it was more effective than anticholinergic drugs for akinesia and rigidity.

• Individual patients with advanced PD who have motor fluctuations and dyskinesia can benefit briefly from the addition of amantadine to the regimen of levodopa.

Nonpharmacologic Management

• Adjunctive therapies focus on neurorehabilitation strategies to enhance neuroplasticity and should be implemented early and continually reassessed as the disease progresses.
• Occupational, physical, and speech therapy should be utilized appropriately based on the patient’s disability and level of functionality.
• Physical activity improves both motor and non-motor symptoms in PD.
• Dance therapy improves motor, gait, and balance as well as quality of life.
• Aerobic exercises, such as treadmill training, boxing, and tai chi, can have similar benefits.
• Cognitive exercises, including crossword puzzles and Sudoku, may also prove to be beneficial, as well as keeping up with current events or utilizing alternative interventions such as music therapy.

Focused Ultrasound Therapy

• Focused ultrasound is a noninvasive, therapeutic technology with the potential to improve the quality of life for patients with tremor dominant Parkinson’s disease.
• This novel technology focuses beams of ultrasonic energy precisely and accurately on targets deep in the brain without damaging surrounding normal tissue.
• Focused ultrasound has the potential to achieve symptomatic relief by making thermal lesions deep in the brain to interrupt circuits involved with tremor and dyskinesia.
• This therapy is now approved by the FDA.

Surgery

• Deep Brain Stimulation: DBS is the most frequently performed surgical procedure for the treatment of advanced PD.
• Bilateral DBS improves motor function in selected patients with advanced typical PD and motor fluctuations.
• The rate of serious adverse events is significantly higher in patients receiving DBS (40%) than in the best medical treatment group (15%).
• The adverse events are directly related to the surgical procedure and include postoperative headache, pain, and infection at the surgical site.
• DBS of the subthalamic nucleus or globus pallidus is more effective than the best medical therapy for improvement of motor function and quality of life for patients with advanced PD, at least in the short term.
• Collaboration with other health care providers is common in the treatment of patients with PD.
• It is important to consult a neurologist before committing patients to medications.
• Consultation with specialists is indicated when patients’ conditions are not responding to treatment or when the disease is progressing.
• Neuropsychological documentation of the precise nature and prevalence of the cognitive deficit has important implications in medical and psychosocial management of patients with PD.
• Hospitalization may be considered for complications such as pneumonia, deep venous thrombosis, and pulmonary embolus.
• Physical therapy can improve mobility and strength, which may help maintain independence and prevent injury.
• Occupational therapy helps improve adaptive equipment and home or workplace adaptations as disability progresses..

Complications and Comorbid Conditions

• Dementia: The prevalence of dementia in PD has been found to be as high as 41%, with incidence rates as high as 78%.

• Older age, PD duration, and severity of parkinsonism may contribute to dementia.

• It is also possible for other dementias, such as Alzheimer disease and vascular dementia, to coexist with PD or for patients with PD to develop milder cognitive impairments that may not meet the criteria for diagnosing dementia.

• PD dementia and dementia with Lewy bodies may be related.

• Psychosis and Hallucinations: Psychosis, a frequent complication of PD, is characterized by visual hallucinations and delusions, often paranoid.

• Hallucinations are most common, affecting up to 40% of patients in advanced stages.

• While dose reduction of antiparkinsonian drugs often resolves hallucinations, stopping all the offending medications is usually not an option, and not all hallucinations are drug related.

• Antiparkinsonian drugs can be reduced or stopped in reverse order of their potency and effectiveness; the sequence begins with anticholinergics then proceeds to COMT inhibitors, then DAs, and then levodopa if all else fails.

• Quetiapine in low doses can be used to manage psychotic symptoms in PD, but studies have failed to demonstrate its efficacy.

• Depression: Depression is the most common psychiatric illness seen in PD and is associated with negative impact on mobility and quality of life.

• There is no clear consensus regarding the use of antidepressants for depression in patients with PD, but there are two concerns regarding the treatment with selective serotonin reuptake inhibitors (SSRIs) in PD: (1) the possibility of increasing motor symptoms and (2) a possible adverse reaction with selegiline when it is used concurrently.

• When these drugs are used, close monitoring is advised.

• Studies have demonstrated benefit over placebo with pramipexole, venlafaxine, and sertraline.

• Cognitive-behavioral therapy can be very helpful.

• Daytime Sleepiness and Fatigue:

• Daytime sleepiness and fatigue are common challenges for patients with PD.

• Sudden somnolence can be a hazard for patients with PD if they are still driving.

• Fatigue appears to be an independent symptom of PD but can certainly overlap with depression and daytime somnolence.

Patient and Family Education and Health Promotion

• Education is essential to help the patient and family understand and gain some control over this chronic and progressive disorder.
• Focused discussions about symptoms and treatments may need to happen with each visit.
• Answering questions and addressing concerns honestly are part of establishing a successful provider–patient relationship.
• Reassurance and encouragement complement medication. Specific points include:
  • Education about medication effectiveness and side effects and drug and diet interactions is important.
  • Normal reactions of anger, depression, and anxiety and social and economic concerns are common, so emotional, psychological, and socioeconomic needs of the patient and family must be addressed.
• Support groups are valuable for emotional support, resources, and education.
• Patients should be encouraged to contact a PD support group and a local PD information and referral center, additionally internet resources are also available for patients with PD.

Explore Parkinson's Disease (PD) prevalence, genetic links, and pathophysiology. Understand dopamine's role in motor function and associated risk factors. Investigate genetic targets for PD treatment and diagnostic accuracy.