Parkinson Disease

Etiology references

1. 1. Ye H, Robak LA, Yu M, Cykowski M, Shulman JM. Genetics and Pathogenesis of Parkinson's Syndrome. Annu Rev Pathol. 2023;18:95-121. doi:10.1146/annurev-pathmechdis-031521-034145

2. 2. Ben-Shlomo Y, Darweesh S, Llibre-Guerra J, Marras C, San Luciano M, Tanner C. The epidemiology of Parkinson's disease. Lancet. 2024;403(10423):283-292. doi:10.1016/S0140-6736(23)01419-8

Symptoms and signs references

1. 1. Aarsland D, Creese B, Politis M, et al. Cognitive decline in Parkinson disease. Nat Rev Neurol. 2017;13(4):217-231. doi:10.1038/nrneurol.2017.27

2. 2. Tomic S, Kuric I, Kuric TG, et al. Seborrheic Dermatitis Is Related to Motor Symptoms in Parkinson's Disease. J Clin Neurol. 2022;18(6):628-634. doi:10.3988/jcn.2022.18.6.628

Levodopa

Levodopa, the metabolic precursor of Levodopa, the metabolic precursor ofdopamine, crosses the blood-brain barrier into the basal ganglia, where it is decarboxylated to form dopamine. Coadministration of the peripheral decarboxylase inhibitor carbidopa prevents . Coadministration of the peripheral decarboxylase inhibitor carbidopa preventslevodopa from being decarboxylated into dopamine outside the brain (peripherally), thus lowering the levodopa dosage required to produce therapeutic levels in the brain and minimizing adverse effects due to dopamine in the peripheral circulation.

Levodopa is most effective at relieving bradykinesia and rigidity and often substantially reduces tremor (2).

Common short-term adverse effects of levodopa are

• Nausea

• Vomiting

• Light-headedness

Common long-term adverse effects include

• Mental and psychiatric abnormalities (eg, delirium with confusion, psychoses, paranoia, visual hallucinations, punding [complex, repetitive, stereotyped behaviors])

• Motor dysfunction (eg, dyskinesias, motor fluctuations)

Hallucinations and paranoia occur most often in older adults and in patients who have cognitive impairment or dementia.

The dose that causes dyskinesias tends to decrease as the disease progresses. Over time, the dose that is needed for therapeutic benefit and the one that causes dyskinesia converge.

To initiate treatment, the dosage of carbidopa/levodopa is increased every 4 to 7 days as tolerated until maximum benefit is reached or adverse effects develop. The risk of adverse effects may be minimized by starting at a low dose and increasing the dosage slowly. Based on the patient's tolerance and response, clinicians can increase the dosage every week up to 2 or 3 tablets 4 or 5 times a day. Frequent dosing (4 to 5 doses a day) is recommended to decrease the effect of fluctuations in plasma levels of To initiate treatment, the dosage of carbidopa/levodopa is increased every 4 to 7 days as tolerated until maximum benefit is reached or adverse effects develop. The risk of adverse effects may be minimized by starting at a low dose and increasing the dosage slowly. Based on the patient's tolerance and response, clinicians can increase the dosage every week up to 2 or 3 tablets 4 or 5 times a day. Frequent dosing (4 to 5 doses a day) is recommended to decrease the effect of fluctuations in plasma levels oflevodopa that can cause motor fluctuations and dyskinesias.

Most patients with Parkinson disease require 400 to 1200 mg a day of levodopa in divided doses every 2 to 5 hours. Preferably, Most patients with Parkinson disease require 400 to 1200 mg a day of levodopa in divided doses every 2 to 5 hours. Preferably,levodopa should not be given with food because protein can reduce absorption of the medication.

If peripheral adverse effects of levodopa (eg, nausea, vomiting, postural light-headedness) predominate, increasing the amount of carbidopa may help. Carbidopa doses up to 150 mg are safe and do not decrease the efficacy of levodopa (3).

A variety of preparation forms of carbidopa/levodopa are available for specific uses, but none is superior to immediate-release carbidopa/levodopa 25/100 mg (A variety of preparation forms of carbidopa/levodopa are available for specific uses, but none is superior to immediate-release carbidopa/levodopa 25/100 mg (1).

• A dissolvable immediate-release oral form of carbidopa/levodopa can be taken without water and is useful for patients who have difficulty swallowing. Doses are the same as for nondissolvable immediate-release A dissolvable immediate-release oral form of carbidopa/levodopa can be taken without water and is useful for patients who have difficulty swallowing. Doses are the same as for nondissolvable immediate-releasecarbidopa/levodopa.

• A controlled-release preparation of carbidopa/levodopa is usually used only to treat nighttime symptoms. When taken with food, absorption can be erratic, and it is present longer in the stomach than immediate-release forms.A controlled-release preparation of carbidopa/levodopa is usually used only to treat nighttime symptoms. When taken with food, absorption can be erratic, and it is present longer in the stomach than immediate-release forms.

• A formulation of levodopa/carbidopa intestinal gel can be given using a pump connected to a feeding tube inserted in the proximal small bowel. This formulation is used as treatment for patients who have severe motor fluctuations and/or dyskinesias that cannot be relieved by medications and who are not candidates for deep brain stimulation.A formulation of levodopa/carbidopa intestinal gel can be given using a pump connected to a feeding tube inserted in the proximal small bowel. This formulation is used as treatment for patients who have severe motor fluctuations and/or dyskinesias that cannot be relieved by medications and who are not candidates for deep brain stimulation.

Occasionally, levodopa must be used to maintain motor function despite levodopa-induced hallucinations or delirium. In such cases, hallucinations and delirium can be treated with antipsychotic medications (oral quetiapine, pimavanserin, or clozapine). These medications, unlike other antipsychotics (eg, risperidone, olanzapine, all typical antipsychotics), do not aggravate parkinsonian symptoms. Although clozapine is most effective, its use is limited because agranulocytosis is a risk (estimated to occur in 1% of patients) and a complete blood count (CBC) must be closely monitored: weekly for 6 months, every 2 weeks for another 6 months, and every 4 weeks thereafter. However, the frequency may vary depending on the white blood cell (WBC) count. -induced hallucinations or delirium. In such cases, hallucinations and delirium can be treated with antipsychotic medications (oral quetiapine, pimavanserin, or clozapine). These medications, unlike other antipsychotics (eg, risperidone, olanzapine, all typical antipsychotics), do not aggravate parkinsonian symptoms. Although clozapine is most effective, its use is limited because agranulocytosis is a risk (estimated to occur in 1% of patients) and a complete blood count (CBC) must be closely monitored: weekly for 6 months, every 2 weeks for another 6 months, and every 4 weeks thereafter. However, the frequency may vary depending on the white blood cell (WBC) count.

Evidence suggests that the atypical antipsychotic pimavanserin is efficacious for psychotic symptoms and does not aggravate parkinsonian symptoms; also medication monitoring does not appear necessary (Evidence suggests that the atypical antipsychotic pimavanserin is efficacious for psychotic symptoms and does not aggravate parkinsonian symptoms; also medication monitoring does not appear necessary (4, 5).

After 2 to 5 years of treatment, most patients experience fluctuations in their response to levodopa, and symptom control may fluctuate unpredictably between effective and ineffective (on-off fluctuations), as response to levodopa starts to wear off. Symptoms may occur before the next scheduled dose (off effects). The dyskinesias and off effects result from a combination of the pharmacokinetic properties of levodopa (particularly its short half-life as an oral medication), and disease progression.

Early in Parkinson disease, there are enough surviving neurons to buffer any oversaturation of dopaminergic receptors in the substantia nigra. As a result, dyskinesias are less likely to occur, and levodopa's therapeutic effect lasts longer because of the reuptake of excessive levodopa and its reutilization. As dopaminergic neurons are further depleted, each dose of levodopa saturates more and more dopamine receptors, resulting in dyskinesias and motor fluctuations because the delivery of levodopa to the substantia nigra becomes dependent on the plasma half life of levodopa (1.5 to 2 hours).

However, dyskinesias result mainly from disease progression and are not directly related to cumulative exposure to levodopa, as previously believed. Disease progression is associated with pulsatile administration of oral levodopa, which sensitizes and changes glutamatergic receptors, especially NMDA (N-methyl-d-aspartate) receptors. Eventually, the period of improvement after each dose shortens, and drug-induced dyskinesias result in swings from akinesia to dyskinesias. Traditionally, such swings are managed by keeping the levodopa dose as low as possible and using dosing intervals as short as every 1 to 2 hours, which are impractical. Alternative methods to decrease the off (akinetic) times include adjunctive use of dopamine agonists, as well as COMT and/or MAO inhibitors; amantadine may help manage dyskinesias.agonists, as well as COMT and/or MAO inhibitors; amantadine may help manage dyskinesias.

Domperidone blocks peripheral dopamine receptors and does not cross the blood-brain barrier to affect the brain. By decreasing the decarboxylation of levodopa to dopamine, domperidone lessens the peripheral adverse effects of levodopa, thereby decreasing nausea, vomiting, and orthostatic hypotension. Domperidone, however, has been associated with serious cardiac risks and is not available in the United States except for investigational use.

Amantadine

Amantadine is most often used to:Amantadine is most often used to:

• Ameliorate dyskinesias secondary to levodopa Ameliorate dyskinesias secondary to levodopa

• Lessen tremors

Amantadine is useful as monotherapy for early, mild parkinsonism but often loses its effectiveness after several months. Amantadine is useful as monotherapy for early, mild parkinsonism but often loses its effectiveness after several months.Amantadine can also be used to augment levodopa’s effects by increasing dopaminergic activity, anticholinergic effects, or both. Amantadine can be helpful in managing dyskinesias secondary to levodopa. can be helpful in managing dyskinesias secondary to levodopa.

Dopamine agonists

These medications directly activate dopamine receptors in the basal ganglia. They include

• PramipexolePramipexole

• RopiniroleRopinirole

• RotigotineRotigotine

• ApomorphineApomorphine

Oral dopamine agonistsOral dopamine agonists can be used as monotherapy but, as such, are rarely effective for more than a few years. Using these medications early in treatment, with small doses of levodopa, may be useful in patients at high risk of dyskinesias and on-off effects (eg, in patients < 60 years). Oral can be used as monotherapy but, as such, are rarely effective for more than a few years. Using these medications early in treatment, with small doses of levodopa, may be useful in patients at high risk of dyskinesias and on-off effects (eg, in patients < 60 years). Oraldopamine agonists may be useful at all stages of the disease, including as adjunctive therapy in later stages, but adverse effects may limit their use. Nearly 40% of patients using dopamine agonists develop impulse control disorders such as compulsive gambling, excessive shopping, hypersexuality, or overeating (6, 7). These adverse effects often require dose reduction or withdrawal of the causative medication and possibly avoidance of the medication class.

PramipexolePramipexole and ropiniroleropinirole, given orally, can be used instead of or with levodopa in early Parkinson disease or can be added to treatment in advanced disease. These medications have a half-life of 6 to 12 hours and can be taken as immediate-release preparations 3 times a day. They can also be taken as sustained-release preparations once/day, helping minimize peaks and troughs in blood levels. Daytime sleepiness is a common adverse effect., given orally, can be used instead of or with levodopa in early Parkinson disease or can be added to treatment in advanced disease. These medications have a half-life of 6 to 12 hours and can be taken as immediate-release preparations 3 times a day. They can also be taken as sustained-release preparations once/day, helping minimize peaks and troughs in blood levels. Daytime sleepiness is a common adverse effect.

RotigotineRotigotine, given transdermally once a day, provides more continuous dopaminergic stimulation than medications given via other routes.

ApomorphineApomorphine is a dopamine agonist used as rescue therapy when akinetic-rigid motor fluctuations are frequent and severe. It can be given sublingually or subcutaneously. Onset of action is rapid (5 to 10 minutes), but duration is short (60 to 90 minutes). Apomorphine can be given up to 5 times a day as needed. A 2-mg test dose is given first to check for agonist used as rescue therapy when akinetic-rigid motor fluctuations are frequent and severe. It can be given sublingually or subcutaneously. Onset of action is rapid (5 to 10 minutes), but duration is short (60 to 90 minutes). Apomorphine can be given up to 5 times a day as needed. A 2-mg test dose is given first to check fororthostatic hypotension. Blood pressure (BP) is checked in the supine and standing positions before treatment and 20, 40, and 60 minutes afterward. Other adverse effects are similar to those of other dopamine agonists. Nausea can be prevented by starting trimethobenzamide 3 days before starting agonists. Nausea can be prevented by starting trimethobenzamide 3 days before startingapomorphine and continuing trimethobenzamide for the first 2 months of treatment.

Apomorphine given by subcutaneous pump is available in some countries; it can be used instead of a levodopa pump in patients who have advanced Parkinson disease and who are not candidates for functional surgery.

Bromocriptine may be used in some countries, but in North America, its use is largely limited to treatment of pituitary adenomas because it increases the risk of cardiac valve fibrosis and pleural fibrosis.Bromocriptine may be used in some countries, but in North America, its use is largely limited to treatment of pituitary adenomas because it increases the risk of cardiac valve fibrosis and pleural fibrosis.

Selective MAO-B inhibitors

Selective MAO-B inhibitors include selegiline and rasagiline.Selective MAO-B inhibitors include selegiline and rasagiline.

SelegilineSelegiline inhibits 1 of the 2 major enzymes that break down dopamine in the brain, thereby prolonging the action of each dose of levodopa. In some patients with mild off effects, in the brain, thereby prolonging the action of each dose of levodopa. In some patients with mild off effects,selegiline helps prolong levodopa’s effectiveness. Used initially as monotherapy, selegiline controls mild symptoms. Nonselective MAO inhibitors yield amphetamine-like metabolites and, at higher doses, may cause a hypertensive crisis when foods containing tyramine (eg, some cheeses) are consumed;at the therapeutic dose listed, Selegiline remains a selective MAO-B inhibitor and dietary restriction is not required. Although virtually free of direct adverse effects, -like metabolites and, at higher doses, may cause a hypertensive crisis when foods containing tyramine (eg, some cheeses) are consumed;at the therapeutic dose listed, Selegiline remains a selective MAO-B inhibitor and dietary restriction is not required. Although virtually free of direct adverse effects,selegiline can potentiate levodopa-induced dyskinesias, mental and psychiatric adverse effects, and nausea, requiring reduction in the levodopa dose. Selegiline is also available in a formulation designed for buccal absorption (zydis-dose. Selegiline is also available in a formulation designed for buccal absorption (zydis-selegiline).

RasagilineRasagiline inhibits the same enzymes as selegiline. It is effective and well-tolerated in early and late disease; uses of inhibits the same enzymes as selegiline. It is effective and well-tolerated in early and late disease; uses ofrasagiline 1 mg orally once a day are similar to those of selegiline. Unlike selegiline, it does not have amphetamine-like metabolites, so theoretically, risk of a hypertensive crisis when patients consume tyramine is lower with rasagiline.

Anticholinergic medications

Anticholinergic medications can be used as monotherapy in early Parkinson disease and later to supplement levodopa. They are most effective for tremor. Doses are increased very slowly. Adverse effects may include cognitive impairment and dry mouth, which are particularly troublesome for older adults. Thus, anticholinergic medications are usually used only in young patients with tremor-predominant Parkinson disease or with some dystonic components. Rarely, they are used as adjunctive treatment in older adults who do not have cognitive impairment or psychiatric disorders.Anticholinergic medications can be used as monotherapy in early Parkinson disease and later to supplement levodopa. They are most effective for tremor. Doses are increased very slowly. Adverse effects may include cognitive impairment and dry mouth, which are particularly troublesome for older adults. Thus, anticholinergic medications are usually used only in young patients with tremor-predominant Parkinson disease or with some dystonic components. Rarely, they are used as adjunctive treatment in older adults who do not have cognitive impairment or psychiatric disorders.

Some studies using a mouse model indicate that use of anticholinergic medications should be limited because they appear to increase tau pathology and neurodegeneration; the degree of increase correlates with the medication's central anticholinergic activity (8, 9).

Commonly used anticholinergic medications include

• BenztropineBenztropine

• TrihexyphenidylTrihexyphenidyl

Antihistamines with anticholinergic effects (eg, diphenhydramine or phentermine ) are occasionally useful for treating tremor.Antihistamines with anticholinergic effects (eg, diphenhydramine or phentermine ) are occasionally useful for treating tremor.

Anticholinergic tricyclic antidepressants (eg, amitriptyline at bedtime), if used for depression, may be useful as an adjunct to Anticholinergic tricyclic antidepressants (eg, amitriptyline at bedtime), if used for depression, may be useful as an adjunct tolevodopa.

Catechol O-methyltransferase (COMT) inhibitors

COMT inhibitor medications (eg, entacapone, tolcapone) inhibit the breakdown of COMT inhibitor medications (eg, entacapone, tolcapone) inhibit the breakdown oflevodopa and dopamine and therefore may be useful as adjuncts to levodopa. They are used commonly in patients who have been taking and therefore may be useful as adjuncts to levodopa. They are used commonly in patients who have been takinglevodopa for a long time when response to levodopa is progressively wearing off at the end of dosing intervals (known as wearing-off effects).

EntacaponeEntacapone can be used in combination with levodopa and carbidopa. can be used in combination with levodopa and carbidopa.

TolcaponeTolcapone is a more potent COMT inhibitor because it can cross the blood-brain barrier; however, it is less commonly used because of the potential for liver toxicity. It is an appropriate option if entacapone does not sufficiently control off effects. Liver enzymes must be monitored periodically. is a more potent COMT inhibitor because it can cross the blood-brain barrier; however, it is less commonly used because of the potential for liver toxicity. It is an appropriate option if entacapone does not sufficiently control off effects. Liver enzymes must be monitored periodically.Tolcapone should be stopped if alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels increase to twice the upper limit of the normal range or higher or if symptoms and signs suggest that the liver is damaged.

Opicapone is a third-generation COMT inhibitor that appears to be effective and safe in patients with Parkinson disease. Unlike tolcapone and like entacapone, Opicapone is a third-generation COMT inhibitor that appears to be effective and safe in patients with Parkinson disease. Unlike tolcapone and like entacapone,opicapone does not require monitoring with periodic laboratory tests or multiple oral dosing.

Surgery

If pharmacotherapy is ineffective and/or has intolerable adverse effects, surgery, including deep brain stimulation and lesional surgery, may be considered.

Deep brain stimulation of the subthalamic nucleus or globus pallidus interna is often recommended for patients with levodopa-induced dyskinesias or significant motor fluctuations; this procedure can modulate overactivity in the basal ganglia and thus decrease parkinsonian symptoms in patients with Parkinson disease (10). For patients with tremor only, stimulation of the ventralis intermediate nucleus of the thalamus is sometimes recommended; however, because most patients also have other symptoms, stimulation of the subthalamic nucleus, which relieves tremor as well as other symptoms, is usually preferred. When the main problem is inadequate control of dyskinesias or when patients have an increased risk of cognitive decline, the globus pallidus interna is a good target.

Lesional surgery aims to stop overactivity directed to the thalamus from the globus pallidus interna; thalamotomy is sometimes done to control tremor in patients with tremor-predominant Parkinson disease. However, lesional surgery is not reversible and cannot be modulated over time; bilateral lesional surgery is not recommended because it can have severe adverse effects such as dysphagia and dysarthria. Lesional surgery involving the subthalamic nucleus is contraindicated because it causes severe ballismus.

Patient selection is the most important factor for successful functional surgery in Parkinson disease. Surgery is usually considered when pharmacotherapy of dyskinesias and/or motor fluctuations is ineffective or the effectiveness is severely limited. Pharmacotherapy may be inadequate because the medication has adverse effects that prevent further increases in the levodopa dose.

Other selection criteria include

• Parkinson disease present for 5 to 15 years

• Patient age < 70 years

• No significant cognitive decline, no affective disorder, and no terminal disease (eg, cancer, chronic renal failure, liver failure, significant cardiopathy), or uncontrolled diabetes mellitus or uncontrolled hypertension

Patients with cognitive impairment, dementia, or a psychiatric disorder are not suitable candidates for surgery because neurosurgery can exacerbate cognitive impairment and psychiatric disorders, and the risk of additional mental impairment outweighs the benefits of any improvement in motor function.

High-intensity focused ultrasound (HIFU)

MR-guided high-intensity focused ultrasound can be used to control severe tremor refractory to medications in patients with Parkinson disease. With this procedure, the ventral intermediate nucleus of the thalamus can be ablated with minimal risk of hemorrhage and infection, which may occur when more invasive neurosurgical procedures are used.

In addition to treatment of tremor, HIFU has shown promise in treating symptoms of bradykinesia and rigidity while reducing the rate of dyskinesias (11). Although HIFU is less invasive than other surgical interventions, deep brain stimulation is favored by most expert clinicians.

Physical and lifestyle measures

Maximizing activity is a goal. Patients should increase daily activities to the greatest extent possible. Physical or occupational therapy, which may involve a regular exercise program, may help promote physical conditioning. Therapists may teach patients adaptive strategies and suggest appropriate adaptations in the home (eg, installing grab bars to reduce the risk of falls).

To prevent or relieve constipation (which may result from Parkinson disease, antiparkinsonian medications, and/or inactivity), patients should consume a high-fiber diet, exercise when possible, and drink adequate amounts of fluids. Dietary supplements (eg, psyllium) and stimulant laxatives (eg, bisacodyl) can help.To prevent or relieve constipation (which may result from Parkinson disease, antiparkinsonian medications, and/or inactivity), patients should consume a high-fiber diet, exercise when possible, and drink adequate amounts of fluids. Dietary supplements (eg, psyllium) and stimulant laxatives (eg, bisacodyl) can help.

Caregiver and end-of-life issues

Because Parkinson disease is progressive, patients eventually need help with normal daily activities. Caregivers should be directed to resources that can help them learn about the physical and psychological effects of Parkinson disease and about ways to help the patient function as well as possible. Because such care is tiring and stressful, caregivers should be encouraged to contact support groups for social and psychological support.

Eventually, most patients become severely disabled and immobile. They may be unable to eat, even with assistance. Because swallowing becomes increasingly difficult, death due to aspiration pneumonia is a risk. For some patients, a nursing home may be the best place for care.

Before people with Parkinson disease are incapacitated, they should establish advance directives, indicating what kind of medical care they want at the end of life.

Treatment references

1. 1. de Bie RMA, Katzenschlager R, Swinnen BEKS, et al. Update on Treatments for Parkinson's Disease Motor Fluctuations - An International Parkinson and Movement Disorder Society Evidence-Based Medicine Review. Mov Disord. 2025;40(5):776-794. doi:10.1002/mds.30162

2. 2. Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020;323(6):548-560. doi:10.1001/jama.2019.22360

3. 3. Brod LS, Aldred JL, Nutt JG. Are high doses of carbidopa a concern? A randomized, clinical trial in Parkinson's disease. . Are high doses of carbidopa a concern? A randomized, clinical trial in Parkinson's disease.Mov Disord. 2012;27(6):750-753. doi:10.1002/mds.24998

4. 4. Müller T. Evaluating pimavanserin tartrate as a treatment in Parkinson's disease. . Evaluating pimavanserin tartrate as a treatment in Parkinson's disease.Expert Opin Pharmacother. 2024;25(15):1999-2003. doi:10.1080/14656566.2024.2417733

5. 5. Cummings J, Isaacson S, Mills R, et al. Pimavanserin for patients with Parkinson's disease psychosis: A randomised, placebo-controlled phase 3 trial, . Pimavanserin for patients with Parkinson's disease psychosis: A randomised, placebo-controlled phase 3 trial,Lancet. 383 (9916):533–540, 2014. doi: 10.1016/S0140-6736(13)62106-6

6. 6. Garcia-Ruiz PJ, Martinez Castrillo JC, Alonso-Canovas A, et al. Impulse control disorder in patients with Parkinson's disease under dopamine agonist therapy: a multicentre study. . Impulse control disorder in patients with Parkinson's disease under dopamine agonist therapy: a multicentre study.J Neurol Neurosurg Psychiatry. 2014;85(8):840-844. doi:10.1136/jnnp-2013-306787

7. 7. Weintraub D, Koester J, Potenza MN, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol. 2010;67(5):589-595. doi:10.1001/archneurol.2010.65

8. 8. Yoshiyama Y, Kojima A, Itoh K, Uchiyama T, Arai K. Anticholinergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model. Neurobiol Dis. 2012;45 (1):329-336. doi: 10.1016/j.nbd.2011.08.017

9. 9. Yoshiyama Y, Kojima A, Itoh K, et al. Does anticholinergic activity affect neuropathology? Implication of neuroinflammation in Alzheimer's disease. Neurodegener Dis. 2015;15(3):140-148. doi: 10.1159/000381484 

10. 10. Bratsos S, Karponis D, Saleh SN. Efficacy and Safety of Deep Brain Stimulation in the Treatment of Parkinson's Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Cureus. 2018;10(10):e3474. Published 2018 Oct 22. doi:10.7759/cureus.3474

11. 11. Vibhor KV, Paul S. Fishman PS, Eisenberg HM, et al. Trial of globus pallidus focused ultrasound ablation in Parkinson's disease. N Engl J Med. 2023;388 (8):683-693. doi: 10.1056/NEJMoa2202721